Soul Eater's Crona, an (if not the) audience favorite, is the Big Bad as of chapter 104.
But is promptly reabsorbed by Asura not too long after.
Akira, when the main character Kaneda must battle his super-powered and tormented friend Tetsuo, who goes on a destructive rampage after his sanity is nearly split from the disturbing mental images that plague his mind after acquiring said super-powers. Eventually, Tetsuo loses control of his powers and transforms into a truly Nightmare Fuelerrific amoeba like blob of flesh and organs that consumes everything in its path. This is an unusual example in that while Kaneda and Tetsuo are best friends, they actually relish fighting each other (mainly because they're friends).
Cyborg 009 has three of them: 0011 (a man who wanted to see his family), 0012 (a woman whose house and memories were manipulated by Black Ghost) and 0013 (who helps the innocent bystanders, punishes criminals, is a Worthy Opponent to Joe and is Driven to Suicide)'
Witchblade has a very Tear Jerker version of this. Most of the show's monsters are Ex Cons, creatures made with Human Resources. It gets heartbreaking when you realize at least one of them not only retained its own mind, but actually is horrified at what it had become and begs The Hero to take them down before anyone else died.
Baldr Force EXE: Ren, who happens to be the dead little sister Tohru forgot he had. And while she's physically dead, her mind and spirit continue to exist, sans body, in the Wired, where her subconscious exhibits itself as a Planet Eater. This results in a major Tearjerker of a finale...
Priscilla in Claymore. She is affected by Horror Hunger, and remembers her parents getting eaten every time she eats someone. More recently, Cassandra.
Hans, the last of the Flamethrower Troopers in Pumpkin Scissors. He was told that the liquid in his armored suit would prevent the flames from hurting him—as it turns out, it just prevented him from feeling the pain. When the war ended, the other troopers took off their suits, and their bodies literally fell into pieces. Physically and mentally numb, he continues to kill on the orders of the Silver Wheel, because starting fires is the only thing that still makes him feel warm, reminding him of the life he once had, and the friends he watched die.
Kaien Shiba and his wife in Bleach. Infested by a parasitic Hollow, they have no control over their bodies and can only watch as the Hollow slaughters their friends and subordinates. In the end, Rukia had to impale her beloved mentor to kill the Hollow and him at the same time. It took years for the resulting trauma to fade.
Sora Inoue, Orihime's older brother. Consumed by loneliness and regrets as years passed, he transformed into a Hollow that sought to destroy everything that caused those feelings of sorrow, namely Orihime and her friends. Even when he temporarily regained control and apologized, he had to die.
A definite Player Punch for Ichigo. He had never realized until that point that Hollows were once people, and when he finds out it's while trying to stop a spirit who died at his family's clinic.
By the same ticket, many Hollows can fall under this category. Driven mad by sorrow and loneliness, they destroy everything they valued in life and only through the purifying blade of a Shinigami can they find release from that cycle.
Similarly to Bleach, the human souls of Akuma in D Gray Man are invisible to everyone but Allen, and they can't stop themselves from killing dozens of people unless someone destroys them. Level 2 demons are intelligent, and they all have a tragic backstory attached.
In Puella Magi Madoka Magica, Sayaka Miki becomes a Witch in the main storyline, as does Madoka Kaname herself during one of the alternate timelines. Given the nature of magic and magical girls in the Puella Magi universe, every Witch counts as this.
Jeff Goldblum's portrayal of the doomed Dr Seth Brundle in The Fly. Much as he tries to hold onto his humanity, the cruel and heartless insect takes over and his desperation to stay human overrides his need to protect Veronica, the love of his life and the mother of his unborn child.
The ending where he holds the gun to his head and silently begs Geena Davis to pull the trigger really drives this home. Total Tear Jerker.
Except, and ironically given later portrayals, Dracula. Lugosi's Count was pure Chaotic Evil. Though even he has a wistful moment in the first film when he says: "To die.. to be truly dead... That must be glorious."
Shaun Of The Dead: When his best friend is turned into a zombie and can't be turned back, Shaun, instead of killing him, locks him up in the storage shed and plays PlayStation with him.
It's toyed with in this case. The implication is that Ed(the aforementioned best friend) is really no worse off than when the movie started.
The depiction of Two-Face in The Dark Knight is particularly heartbreaking.
In the Hive Series, Raven hasa flashback in Aftershock involving her being forced to kill her best friend, Tolya, who had lost it and was now trying to kill her.
It doesn't get more tragic than the Creature from Frankenstein. Created and immediately abandoned by its creator for being ugly, before it even really wakes up. Made innocent, his nature is soon twisted by circumstance into something horrible and evil, alone, wretched and violent. The worst part, however, is that he knows exactly how wicked he has become but knows he cannot change.
The novel for Coraline has The Other Father, who was created to love and care, and was mutated by the Other Mother to fight Coraline. This gets even worse in the movie, since it's implied that all of the Other counterparts have been with the Other Mother since she started the eat-children's-souls thing, and have just been modified to fit their roles. They don't want to hurt anyone, just to fill their parts as people to care and love the children. Other Father gets mutated and forced to fight Coraline, Spink and Forcible are turned into taffy-like beasts, and it's implied that Other Old Man (Mr.Bobo/Bobinsky in the movie) was EATEN by his rats.
Many in the Deltora Quest series, the most prominent of which was the fate given to Doran the Dragonlover. He was forced to become the Guardian of a Sister - the very thing he set out to destroy many, many years ago.
Diran's best friend from his acolyte days comes back as a werewolf (anathema to members of their church) in The Blade Of The Flame books.
Werewolf Remus Lupin in Harry Potter, although he's only like this once a month. The rest of the time he's safe, good, and in his right mind.
Even then, it's only if he doesn't have any Wolfsbane potion that the wolf takes over. Too bad said Wolfsbane potion is a relatively recent invention that wasn't available when he was first bitten as a child.
This occurs in Galaxy in Flames, when Loken meets Kharn after the latter fell to chaos. Kharn had been previously established as a noble and loyal warrior, acting equerry to his Primarch Angron and tempering his rages. Now he's just a snarling, hate-filled... monster - for lack of a better word. When Loken asks what has been done to him, Kharn regains his sanity for a moment and expresses regret, but "there is no going back". Then he goes under again and attacks and Loken has no choice but to try and kill him (of course it doesn't take).
Vrasta the "Wrong One" Fammin in Chronicles of the Emerged World has feelings, dreams and a conscience, but when his name is spelled he's compelled to obey orders and eventually kills his new-found friend Laio.
In The Dresden Files book Changes, Harry Dresden must kill Susan, the mother of his child, when she starts turning into a red court vampire. A bit of a subversion, since Martin intentionally enraged her to the point where she would turn, because it was their only way out. And to destroy every red court vampire in existence.
Even worse than that in the long run is the means by which he gets there. He seeks out Mab, and asks to be her vassal. Nearly aborted by his Thanatos Gambit. It takes a whole book for Harry to figure out what happened and help salvage the situation.
Thomas in Turn Coat, after Shagnasty tortured him. Though your Your Mileage May Vary considering his disturbing nature.
The Moomins has the Groke, who, particularly in her animated form, terrifies both the readers/viewers and the inhabitants of Moominvalley. However, as "Moominland Midwinter" proves, she's really not a bad person; she's just terribly cold and lonely, and all she wants is a friend, as Moomintroll himself realises. Unfortunately, she's apparently some kind of embodiment of winter, meaning she's freezing cold to the touch and can't ever be allowed to hug someone, or she'll probably freeze them to death entirely by accident. So she just roams silently through the valley, hoping to be warm but doomed to always be cold.
Live Action TV
Season 8 of Smallville introduces us to Davis Bloome a likeable paramedic, and possible Love Interest for Clark's best friend, Chloe Sullivan. Unfortunately, Davis has alien Serial Killer and Person of Mass Destruction Doomsday trapped inside of him. Davis shifts into Doomsday more and more frequently as the show progresses, all while trying to repress his Superpowered Evil Side while committing murders (of criminals) in his human form. Ultimately, it destroys his sanity and he has to be put down for his own good and everyone else's; Davis is killed and Doomsday is separated from him and buried alive.
Mitchell from Being Human post season 2 after killing the Box Tunnel 20 and slowly spirals out of control till his suicide at the end of season 3.
Happens to many characters over the course of the The Walking Dead series. Given how often this happens in the show, it's still no less heartbreaking. Notable mentions include Shane, Amy (Andrea's sister), Penny (the Governor's daughter), Sophia (Carol's daughter), and most recently, Merle and Andrea.
Most Dungeons & Dragons monsters are just plain rotters, but the ones you find in Ravenloftalways have dreadful backstories. Strahd Von Zarovich just wanted the love of a young woman, and became a vampire to get it. Victor von Mordenheim just wants to restore his dead wife to life, and his creation Adam just wants to be loved and accepted (and make Mordenheim's life hell). And as for Lord Soth, well... more on him below.
And It's more of a Then Let Me Be Evil moment. She was thrown to the Zerg, she's just playing the part because of it
While the original game largely avoids this, Wings of Liberty employs it with regards to Raynor's relationship with her. Especially prominent just prior to the campaign's finale when the remnants of Kerrigan's uninfested personality whisper encouragement to Raynor. Then promptly averted when they do save her.
Although all is not well, come the sequel. Though Kerrigan is indeed de-infested, she admits that she can still contact the zerg, and her relationship with Raynor is strained at best. (As for the rest of the Terrans, they're keeping her locked in a grade-A biological quarantine cell.) Then the Dominion attacks the facility, and while the two fight together well and the scars seem to be healing over, they are separated and Raynor is captured by the Dominion. Kerrigan wants to stay and wait for him, but the rest of her allies abandon her — and then a Dominion broadcast airs that claims that Raynor was interrogated and summarily executed. With nothing else holding her back, she goes back to the zerg, re-assuming her infested form by becoming the "primal Queen of Blades" on Zerus, the original zerg homeworld.
So, in short: regular human -> tragic monster -> tragic human -> something which is mostly tragic, and mostly a monster (and very angry).
Cave Story: Toroko, an innocent villager, becomes a raving monster after being force-fed a nasty red flower by Balrog under the wicked Doctor's orders. Before bitching about Balrog, keep in mind who's the thrall and who's the Complete Monster.
Rundas, Gandrayda and Ghor in Metroid Prime 3: Corruption. Also, if you're not careful, Samus. To be more specific, in the beginning Dark Samus infects all four bounty hunters with Phazon.
Then, on Elysia, you fight Ghor. You return to your ship, only to find Ghor trying to destroy it. He spots you, and tells you you're just in time. He throws the ship at you, and the boss battle begins soon after. His battle suit explodes, and then Dark Samus absorbs him.
Then, on the Space Pirate Homeworld, you fight Gandrayda. She disguises herself as a federation trooper, then tries to shoot Samus In the Back. After the boss battle, she changes first into Rundas, then into Ghor, and finally into Samus. At this point, Samus can't bear to look as Dark Samus absorbs Gandrayda.
In Prey, your girlfriend Jen's upper body is grafted onto the body of a monster. This is a very disturbing sequence, as not only was Jen the de facto Distressed Damsel up to this point, but she's also not brainwashed or possessed in any way. The monster half simply has a mind of its own, thus forcing you to kill your still very much alive girlfriend, or be eaten.
"Tommy? I can't feel my legs..."
The Elder Scrolls IV Oblivion's Shivering Isles expansion: Your old mentor, Sheogorath, turns out to have been an alter ego of Big Bad Jyggalag all along and, due to a curse, he is forced to revert to Jyggalag at the end of every era and destroy his own world. In the final quest, you have to kill him before he carries out these plans, although as the guy on the Tear Jerker page commented, this means "you kill a god, so it doubles as the player's Crowning Moment of Awesome".
Also, on the way to the Big Bad of the Mage's Guild quests, you are sent to rescue an informant who is spying on the necromancers. You find him... a little too late, after he's been turned into a zombie.
In Final Fantasy IV, Edge's parents are transformed into monsters controlled by one of Rubicante's minions. They eventually recover their minds and commit suicide. Rubicante does express sorrow for this, and apologizes to Edge. The minion did this against the orders of Rubicante's, who implies he would have killed the minion for this were he still alive.
The whale-like destroyer Sin in Final Fantasy X is the shell around the Final Aeon that defeated it last; in this case, Tidus's father Jecht.
And again in the remake Castlevania: The Dracula X Chronicles, although the mood is kind of sidetracked since, instead of being turned into a skull sorceress as in the original, Annette is instead transformed into a Stripperiffic succubus in cleavage-barring black lingerie, because Evil Is Sexy.
Dracula in many of the games qualifies as such, as he turned into him in the first place because of both loves of his life's deaths.
In Alien Syndrome for the Wii, you have to fight the terribly mutated form of the Aileen's husband.
In Resident Evil Code Veronica, Steve is infected with a form of the virus that mutates him into a giant hulking monster that Claire has to take down.
Another one of the bosses, "Nosferatu", is the product of a botched experiment with the Veronica-T virus on Alexander, Alfred's father.
William Birkin in Resident Evil 2 is also kind of one of these. Mortally wounded by Umbrella's agents, he injected himself with The Virus out of desperation, turning him into his tragic One-Winged Angel form. Mitigated somewhat by how before this transformed, the human William Birkin was a downright evil man.
In Resident Evil 3 Nemesis, you encounter a UBCS officer named Murphy who is turning into a zombie. Either Carlos or Nicolai puts him out of his misery.
Lisa Trevor from the remake of Resident Evil. She immediately puts all the above to shame as she was the helpless 14 year old daughter of the mansion's creator, and she and her mother were made into test subjects by Umbrella against their will. Her mother died from being infected with the T-Virus, but Lisa sadly survived and was then proceeded to be injected with the Nemesis virus (which was used to produce the walking nightmare in Resident Evil 3 of the same name) and upon its injection, it created the G-Virus in her body. Making matters worse, even with her mind completely deteriorated and now orphaned, she longed to find her mother in a mansion now completely ridden with monsters...alone....
All the zombies/Ganados/Majini from all the games are these. If the viruses and Las Plagas parasites hadn't broken out, they wouldn't have become these... things... Special mention goes to the credits of Resident Evil 4, which shows a number of the Ganados living happy normal lives in a hand-drawn slideshow complete with peaceful music. About halfway through the music turns ominous, and you begin to see scenes of the villagers clutching their throats in agony and eventually killing one another.
In Digital Devil Saga, this happens not once, not twice, but three times. The first is when Jinana loses herself to hunger because she hasn't eaten since the events in the game began; the second when Lupa is hit with a nasty technique from Varin Omega that causes him to lose control and attack his own men, not to mention the protagonists; and in the second game Heat, after his Heel Face Turn. Heat's case is particularly heartbreaking, since it's implied ingame that he knows he's a monster and is committing suicide by True Companions. In the first and third cases, the only cure was to be heavily mortally wounded. In the second case Lupa was too weak to even manage that.
In the upgraded version of Baldur's Gate 2: Throne of Bhaal the Big Bad turns your sister Imoen into the mindless Slayer form and sets her on you. She will revert and rejoin your party if you leave her long enough, unfortunately the Big Bad also sets Jon Irenicus, Bodai and a fallen Solar on you at the same time. Taking on all four at once is very difficult, and she's the easiest to kill...
This is how Imoen dies in the novelization of the game.
This only happens if you use the Ascension mod, not in the bare game.
It can seem like this is going to happen in the main Baldur's Gate II storyline, too: if your character has a romantic interest, and you're far enough along the romance storyline, they will be kidnapped and vampirised by Bodhi. While you will have to kill them, there's a way to bring them back: take their corpse and Bodhi's heart to the ruined Temple of Amaunator, then stick them in a specific idol - instant cure. You don't find this out until after you've killed them, though.
Odin Sphere has two examples: The first is Belial, a dragon that started off rather friendly but eventually becomes a mindless slave. The other is Ingway, who transforms into Darkova at the end of Velvet's chapter; though able to return to normal form after the first transformation, Ingway fully transforms just in time for the boss run final book of the game. Oddly enough, to get the best ending you have to fight him with Cornelius, his sister's boyfriend. Fighting him with his sister will result in the bad ending — and fighting him with his love interest leads to both the bad ending and a big time Smite Me, O Mighty Smiter.
It is heavily implied that the sarge nearly immediately succumbed to the virus, and was leading your character (and the rest of the military force) on the entire time. So this isn't really a case of that at all.
There's also evidence saying that he was converted by Bertruger sometime after (one theory places the time at when his transmission is cut off while yelling at you for disobeying orders), and that his attempts to call for backup were just Genre Blindness.
In the first-person shooter Area 51, one of your teammates succumbs to The Virus about 1/4th of the way through the game, turning into a mutant and forcing you to fight and kill him.
And you yourself partially turn into a mutant halfway through the game.
The game over screen for the original arcade Area 51 game showed the protagonist morphing into one of the alien mutants, having been infected with The Virus.
In Quake IV, Lt. Voss, your squad leader, gets Stroggified and turned into a mech-like boss monster about 1/2 way through the game.
The stroggified Kane may be considered one of these, since his cybernetic makeover is permanent, although he still has control over himself, making him a Phlebotinum Rebel.
Cheryl/Alessa becomes a tragic monster if you don't unlock the motorcycle gas tank and hereby allow Kaufmann to obtain the Aglaophotis vial, ie exorcism phlebotinum. Cue Downer Ending. Luckily not as much a Guide Dang It as the "+ " ending.
Most of the monsters in Silent Hill can be interpreted this way. For all we know they're human souls bound to monstruous bodies as punishment. Even Pyramid Head seems to be punished by wearing his signature uncomfortable-looking helmet. It's even easier to see things this way in games where the monsters are easy to beat, as the player character rampages around, shooting any helpless freaks they find.
Valkyrie Profile: near the start, Princess Jelanda is transformed into some kind of undead demon and you have to kill her. Then she proceeds to join your party. Later, Lezard transforms Lorenta's husband into a monster, and you are forced to kill him. Also, a certain boss in the first game is revealed to be a childhood friend of the main character of the prequel.
In Final Fantasy Crystal Chronicles, the player gets the option to become friends with De Nam, a selkie you meet in the Shella. He's a scholar and wishes to find a way for humans to live alongside of the miasma, so he heads to the swamp areas of Conall Curach and starts drinking the miasma infested waters. He sends you letters, telling you how his research is going, being overall hopefull about the whole thing. His very last letter is written in a broken manner for you to come to Conall Curach. You can't find him there, but you can run around and beat the monsters as per normal. Eventually you come across a monster who, after you beat it, drops a "Worn Bandanna". Inscribed on the bandanna is De Nam's name. GUESS WHO YOU JUST SLAUGHTERED?
Another Crystal Chronicles example, adding to the De Nam thing, it's heavily implied that that the humanoid enemies, such as Skeletons and Sahagins, a fair bit of them are mutated humans, driven insane by miasma and hopelessness. Have fun playing through Tida and Conall Curach now!
In Onimusha: Dawn of Dreams, you must fight Ohatsu when she has been possessed by the Genma. Tragic music even plays during the battle.
Legend Of Legaia has Gaza, a mighty swordsman. After being defeated by party, he is taken away by Songi, one of the main antagonists. Later, Gaza shows up again, this time under the control of Sim-seru. He turns into a monster, which the party has to defeat. Gaza is injured fatally, but he makes a noble sacrifice to save his town in his last breath.
Depending on how you interpret things, Prince Cort is also an example of this. He might have been wiling, though the game also notes that Rogue Seru are capable of possessing unwilling hosts as well. It never stays clear whether he was Brainwashed and Crazy or evil all along and * really* evil after getting a Rogue Seru. Fortunately for Noa, he gets a second chance after all, but at the time you fight the monster form in the last boss fight, the heroes are under a different impression.
Cort is a small fry compared to THE ENTIRE TOWN OF CONKRAM! Thanks to the Mist being spread from the Absolute Fortress, the Sim-Seru presented to the King during Noa's backstory began to grow in an unstable fashion, eventually absorbing the entire town. By the time you get there, everyone there has become a part of the massive beast, and the King and Queen both help the party prepare to storm the Absolute Fortress with full knowledge that the result is a massive Mercy Kill.
In one of the minor quests in Legend of Mana, one of the professors of the magic university is looking for his brother, who was out exploring a snowfield for faerie treasure. By the time we get there, the professor's brother has turned himself into a snow monster in order to survive, which you have to kill in order to complete the quest.
This list would not be complete without Ryoji Mochizuki of Persona 3, who turns out to be the Anthromorphized avatar of the spirit of Death, Nyx Avatar. Fully aware that he's doomed to kill everyone on Earth, he gives your party the chance to wipe their own memories of the past year, just in time for the end of the world. Made even more tragic by the fact that he's actually rather fond of the world now, having spent 10 years trapped inside the main character. The battle against him has him spouting off Tarot card lessons in a defeated sounding, near emotionless voice all while bemoaning how "It's useless.". He's right.
The new Persona 3 Portable throws an even more tragic twist into the situation: if you pick the female version of the Main Character, Ryoji becomes an S-Link with romantic potential. So, not only is he forced to bring forth the end of the world he's fond of, he's forced to fight the girl he loves as well and she dies to seal Erebus just as the original MC from the original Persona 3 game did.
Done to death in Metal Gear 2 Solid Snake, which had the first two of its three climactic boss battles with the protagonist's best friend. Metal Gear Solid called back to it, only now the best friend is a crazy semi-ninja.
Done very well in Fire Emblem: Path of Radiance, where King Ashnard of Daein uses Izuka's drug to warp the mind of the Goldoan prince Rajaion and force him to remain permanently in dragon form, so he could use him as a personal mount. This causes Ena - Rajaion's fiancee - to find work under Ashnard in an attempt to get close to Rajaion, which in turn causes Nasir (Ena's grandfather) to spy on your party for Daein. Ashnard took advantage of both Nasir and Ena, using the former to steal the MacGuffin he needs for his plans from your party, and the latter in a Uriah Gambit when he orders her to attack your party, thus bringing this trope into play as you're forced to fight Ena and treat your former friend Nasir as a prisoner of war.
An even better example of this trope from that game would be General Shiharam, a.k.a. Jill's father, though he is not literally a monster. The conversations after the battle push it straight into the territory of an enormous Tear Jerker. Especially Haar's reaction to it, and Jill's conversation with the peasant woman.
In Fire Emblem: Blazing Sword (Just Fire Emblem in the Western releases), after Eliwood obtains the dragon-slaying swordDurandal, he is greeted by an enormous ice dragon and is driven by the sword to kill it. Then the Big Bad Nergal shows up to rub his face in the fact that he has just killed Ninian, the girl he (most likely) loved, but at the very least he knew she had trusted and loved him. Nergal had forced Ninian to shift to her true, dragon form, but, despite having the mind of a beast, her desire to be with Eliwood was strong enough to make her seek him out. Still a Tear Jerker, even knowing the ending.
Let's not forget Fire Emblem: Sacred Stones where it turns out the Big Bad is actually the two main characters' meek childhood friend possessed by the spirit of an evil demon. To make matters worse, if you decided to follow Eirika, you learn that the villain is actually in love with her and, by the time the final chapter rolls around, they're forced to try and kill the other
Happens In Parasite Eve to the police dog, Sheeva. She goes berserk from Eve's influence and mutates into a 3-headed beast. To make it even more tragic, Ben, her 8 year old friend is forced to kill her.
Melissa Pierce herself qualifies, as all she wanted was to be a renowned opera singer and was very excited about getting the role, and was easily manipulated by people she trusted. Makes one detest Klamp and Eve even more.
In F.E.A.R. 2, You have to fight Sgt.Keegan, who has gained all your powers, turned into some sort of ghoul, and is insane because Alma likes you more than him. While Alma rapes you.
City of Heroes does this in a few arcs. The Terra arc features a strange case in which you must protect an environmental terrorist named Terra who used to know the Hamidon when he was still human. She is given a serum that eventually turns her into a monstrous Devoured and you have to beat her down. It's never explained if she can be helped at all.
The end of the Lady Grey taskforce forces you to fight the universe's greatest hero, Hero-1, who disappeared when he escaped to the Rikti homeworld and in the eight years since was turned into a horrific Rikti monster named "The Honoree". Not helping matters is that despite the extensive Rikti mind control in place, the act of fighting heroes starts to crack it, but only enough that he is helpless to stop himself from fighting you while crying out in horror at what has happened to him. Upon defeat the mind control is restored and the Rikti teleport him back, so he remains stuck with this fate for the present. The last issue of the City of Heroes comic book also featured this story arc.
One Malta Ops mission arc has the player meet a woman who is trying to investigate the disappearance of her son Joe, a convict who'd begun to turn his life around in prison. Pursuing the investigation ultimately leads the player to a lab in which Malta Operatives have removed Joe's brain and put it into a Humongous Mecha. The player is then obliged to fight the "Titan called Joe" while Joe's voice cries out in horror from the robot. At the conclusion of the mission, the player's contact laments that Joe could not be saved.
In Final Fantasy Tactics, the protagonist's brother Zalbag is teleported to a place of unknown horror by a Zodiac Demon. He reappears a few battles later and is forced by the Big Bad to fight his brother. Zalbag cannot control his body, but is still self-aware, and begs Ramza to kill him.
Wiegraf could also qualify as one, although his status as That One Boss may garner a little less sympathy for him...
Everyone that's not Ace from Ruby Quest probably counts, as the facility used to be a place where the blind received medical treatment. Thinking about this too hard is not recommended.
In The Adventures Of Rad Gravity, the apparent Big Bad is Agathos, a former human who has been mutated into a giant brain. After you defeat him, he returns to human form and reveals that the real big bad is your sidekick Kakos, who manipulated you into reactivating the evil Compuminds that Agathos shut down.
In Skies Of Arcadia, Drachma spends most of the game chasing after an arcwhale that killed his son (in his introduction, he chastises the main characters because they needed rescue, and doing so caused him to lose track of the whale). At the end of the Purple dungeon, you find him sitting peaceably next to the whale as he takes his last breaths. He's finally realized he shouldn't blame the creature for his son's death — the ancient Purple civilization rammed their Moon Crystal into his forehead to make him their Gigas, and pain and immortalityhave driven him mad.
Popular in Chris Roberts games. The trope makes its appearance in Wing Commander III, with Hobbes, and is either played straight or subverted in Wing Commander IV, depending on when you choose to defect from Confed.
The Exsphere monsters ("Exbelua") in Tales Of Symphonia, who are regular humans turned into grotesque monsters. Played with a bit as the first time you fight one, the characters don't know that they're fighting a friend (Genis' friend Marble) until it's mortally wounded, but they get hit hard by the horror once they find out and cannot bring themselves to fight any other attacking Exsphere monsters. Played straighter in Regal's backstory, as when his love Alicia was turned into a monster, he knew it was her he was fighting.
We also have (Kratos' wife/Lloyd's mother Anna) in a flashback.
However, one of them (Dorr's wife Clara) actually can be saved in a sidequest.
Belius from Tales Of Vesperia is the epitome of this trope. From her, Estelle learns the hard way that her healing artes don't have a positive effect on an Entelexeia's sanity.
Oh man, it's like the entire point of Mother 3. That cute little family of friendly dinosaur-dragons you play with in the prologue? One of the parents is turned into an aggressive, fire-spewing cyborg who kills your own mother, only about half a day since you saw it last. How about your excitable, friendly twin brother? Killed by aforementioned cyborg, is brought back to life as one himself with his emotions and memories wiped, and forced to fight against his own father and brother. Plenty of other animals get this chimerical treatment- look at some of the enemies' faces and tell me they're not screaming. The song's called Tragic Reconstruction for a reason, y'know.
From Klonoa there's Leorina, after she collects the four Elements, the power of sorrow engulfs her and mutates her into Cursed Leorina, a creature best described as a giant bird-like creature with small-fairy like wings and a and an extremely creepy roar. She turns normal after you defeat her, thought
From Breath of Fire I, we have your angelic sister - she returns near the end of the game after having been absent since the prologue, but is under the Man Behind the Man's mind control, and is eventually slain by the heroes in her dragon form.
Definitely the entire point of .hack//G.U.. Let's start from the beginning: Haseo's best friend Shino is comatosed, his newly acquired allies start suffering left right and center. The protagonist also becomes entangled in a Batman Gambit (and is an Unwitting Pawn himself), and finally he gets a shot at killing the true culprit after chasing false ends. This is what the true culprit, Ovanwanted from the beginning, launching a convoluted plan to have Haseo kill him. Why? The Corruption has gotten to him and has resulted in a comatose little sister. He has the required cure that will bring everyone back, but it requires a Heroic Sacrifice, and he knows that I Cannot Self-Terminate. By the time Haseo (and by extension, you, the player) knows about this, you cannot help but feel sorry for the guy.
Penumbra features a certain character becoming infected with the virus, forcing you to kill them. Subverted, as Clarence, your own lovely strain of virus, only makes Amabel LOOK like one of the monsters. Once you bash her head in with a steel brick, Clarence reveals your tragic mistake, and pushes himself from Magnificent Bastard to Complete Monster in record time.
It is also suddenly revealed that Red was also an infected, which is why he couldn't commit suicide: The hivemind wouldn't allow it.
Lady, aka Grace Garland from Shadow Hearts: From The New World. Sacrificing her soul to save her dying brother had the undesirable aftereffect of turning her into a soulless, almost mindless killing machine hellbent on destroying the world.
Also from that game, Edna Capone, Al Capone's sister. Her lover Ricardo must kill her after she is brought back as a creature of Malice by Lady.
Brink from Torchlight. An NPC who joins as an ally near the start of the game, the Big Bad turns him into the first boss via The Corruption, and the player is forced to kill him. Partially subverted as the player character doesn't know Brink for very long at all. However, the NPC ally whom Brink was fighting alongside with at the very start of the game definitely seems distraught after his death.
Especially the Big Daddies. Watching how gentle they can be with the Little Sisters has been known to give gamers pause in killing them, and the forlorn way they go wandering when no Little Sisters are around is just sad. The fact that they are brainwashed and not acting on their own choices just makes it worse.
If you followed the ARG, then Mark Meltzer. A chap whose daughter was taken from the surface, in order to be made into a Little Sister. Meltzer searched for her, stumbled upon Rapture, and was given a choice to either be killed, or stay with his daughter forever...as a Big Daddy. Guess what he chose. And the worse part? ''You don't even know it's him until you've killed him.
Handymen are cyborg monstrosities created from people who were sick, disabled or invalid — sometimes against their will, sometimes in hopes of being cured. The result is a monster that knows what a monster it is, can no longer interact safely with humans, and is in constant (and vocal) pain thanks to the crude attempt at implanting its remaining organs into the new body. Worse still, they're also prone to fits of berserk rage induced by this pain, one of the reasons why they're so dangerous in combat.
The Dalish Grey Warden's game starts with them exploring with childhood friend Tamlen. Said childhood friend gets a little too close to an Artifact of Doom and the Warden wakes up three days later apparently found alone and with the taint and a high fever and is taken off by Duncan to be put through the Joining, which will suppress it (for a few decades, anyhow) if they survive - Tamlen gets left for dead not only by Duncan but his and the Warden's whole tribe. Guess who pays the Warden a surprise visit halfway through the game as a ghoul going insane from progressive taint and begging his old bestie for a Mercy Kill.
Quite similar to the Dalish Elf's case is Danyla in the Brecilian Forest, a missing member the Dalish clan from the Nature Of The Beast quest whose husband asks the Warden to search for her as a side mission. She's succumbed to the werewolf curse and is still barely there when she's found, begging the Warden to put her out of her misery and take her scarf back to her husband before losing it and attacking.
And don't get started on Broodmothers.
Arguably the Archdemon himself. There are no reliable sources in the game describing what the Tevintran Old Gods were really like (the Chantry is hardly unbiased on the subject), but to reiterate the point above: the taint really messes you up.
In Dragon Age II, the Legacy DLC has Larius, a half-insane ghoul who used to be the Warden-Commander of the Free Marches. He is the sad result of what fate eventually awaits all Grey Wardens and the reason why they embark on The Calling to prevent themselves from fully succumbing to ghoulification. He unfortunately survived this last stand and has been left to wander the Deep Roads, utterly ignored by the rest of the horde.
His fate becomes even worse if Hawke allies with him against Janeka, as it's heavily implied that he becomes possessed by Corypheus, an Ancient Tevinter Magister and one of the first Darkspawn.
The final boss of the original Gungrave is actually Big Daddy, who in the main character Grave's human life was the closest thing he had to a father and a mentor figure. Harry, having overthrown and taken control of The Syndicate, had who-knows-how-many experiments performed on Big Daddy while he was still alive until he reached his present state—a giant, twisted blue monster locked up at the very top of Millenion's Tower. He no longer has any will of his own or memories of who he used to be—and now Grave must kill the father that never even got to really meet or know his own biological daughter (Mika), the very girl whom Grave serves as Guardian for her.
In Kingdom Hearts Maleficent leads Riku on to believe that she can help him save Kairi and that Sora has abandoned him. He confronts Sora multiple times over the course of the game and eventually leads to Riku having his body taken over by Ansem when he agrees to give in to the darkness.
All the Nobodies and members of Organization XIII in particular qualify, as they're the way they are not of their own choice, and most of them are shown to have been perfectly good people before they became Nobodies.
Golden Sun The Lost Age does this with the last boss, the 3-headed Doom Dragon, which is made of Kyle (Issac's dad) and Felix and Jenna's parents. They got better at the end thanks to the massive ammount of Psynergy emitted from the Mars Star, so it's all good.
In System Shock 2 the Many has turned 98% of the Von Braun's crew into its mindless monstrocities. They weren't responsible for what happened, but you still had to kill them anyway.
The same could be said for in the first game when you had to deal with SHODAN's minions, whom she infected with her mutant viruses. Edward Diego had you remove her ethical constraints, and how does SHODAN play him back? By making him one of her zombie slaves!
One boss monster in Neverwinter Nights 2 Mask of the Betrayer is the long-lost mother one of one of your party members. You don't find out until after defeating her, though. The bit while fighting her where she possesses one of your party members also qualifies.
A few of the villains, (hell an entire race) qualify as this in the Mass Effect series.
Matriarch Benezia is under Reaperindoctrination, meaning her free will has basically been destroyed by the Reaper. And she joined Saren to try to persuade him from his dark path. If it hadn't been for Sovereign, it might have worked. The Collectors were once Protheans, the last race destroyed by the Reapers, who the Reapers corrupted and turned into bug-like monsters, forced to do their bidding.
Saren doesn't really count as he was a monster before being indoctrinated.
Many people think the Rachni were also victims of Reaper indoctrination.
In Mass Effect 2, the asari agent does state that the rachni queen's own memories and nature point towards the rachni having been mind-controlled, and Shepard's immediate suggestion is that the Reapers were responsible. Legion states that Nazara, aka Sovereign, did seek out other allies before coming to the Geth, so it's quite possible the rachni were an early, failed attempt.
In the "Overlord" DLC, David Archer. Not only was he forced by his brother to become a VI figurehead in an attempt to unite the geth, he's also autistic, so he doesn't fully understand what's happening to him. The VI's shrieks of static you hear throughout the entire set of missions are "MAKE IT STOP!"
In Star Fox Assault, General Pepper, who begs for you to kill him during the entire fight as his body and ship are controlled by the aparoids.
In Dark Chronicle, after you defeat Gaspard at the base of Mt. Gundor, he sees the error of siding with Emperor Griffon and turns to walk away, wishing you well, but before he leaves, Griffon telepathically chastises Gaspard and takes control of him, and morphs him into Ultimate Flame Demon Gaspard, who you must fight to the death.
In Fable III, the final boss is your friend and mentor, Walter Beck, who is possessed by The Crawler. His Boss Banter alternates between raving about how he is going to horrifically kill all of the people of Albion and begging you to put him out of his misery.
Dissidia hints that Sephiroth is one, as Cecil, in a pre-battle quote against Sephiroth, mentions that there's "sorrow in (Sephiroth's) wintery eyes."
Mithala in Aquaria was revered as the forefather of the Mithalan civilization. Then the local Path of Inspiration took over and the rites took a darker turn. Instead of food, they brought worshippers. Eventually, he was driven insane by hunger and accepted the "offering". The cult fed him the entire civilization, turning him into a Womb Level.
Kainé becomes this in the third and fourth endings as a result of the Shade in her body taking control. She becomes the True Final Boss in these ending paths. You then have the choice of either killing her and ending her pain as she had originally wanted or sacrificing your entire existence to restore her to a fully human form.
Several of the Shades fought as bosses also turn out to be a lot more sympathetic in New Game Plus, when you can understand what they're saying.
Vindictus: Ingkells. When he and all the soldiers of Ortel Castle become so overcome with despair that they drink a potion laced with Bloody Shade, Ingkells turns into a furious monster. Learning of this act is one of the most poignant moments in Vindictus' story. Ingkells, however, is unique in that he actually chose to become a monster. However, the fact that he felt enough despair and fury to be driven to such an action makes it all the more tragic..
In The Lord of the Rings Online, the Ranger Amdir, who you spend the first parts of the game trying to help as a Hobbit or a Man after he is stabbed with a Nazgūl's morgul-blade during the introductory sequence, becomes one of the Cargūl, lesser wraiths in red who are slaves of the Nazgūl, after succumbing to the effects of the weapon. Book 1, Chapter 1, your very first quest in the Epic storyline after completing the Intro and the Prologue, consists of finding and killing Amdir, who is lost to Darkness at this point.
In Video Game/Xenoblade, the majority of the High Entia race ends up like this, being devolved into Telethia by the Big Bad and robbed of their sentience so he can use them to enact his plan to eradicate all life on the Bionis. Made more tragic if you had bothered to do quests for the victims beforehand, and still more tragic when their surviving friends and family ask you to give them a Mercy Kill, often after describing an account of said victims having protected them even in their warped state.
Asura's Wrath: Wrath Asura, the result of seeing a little girl that looked just like his daughter die after being slaughtered by Olga of the Seven Deities. Made much more obvious with his battle theme, Bonds.