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Christa from The Walking Dead game seems to be like this towards Clementine, and her boyfriend, Omid. Carley is implied to have been this towards her, too.
The Pokémon Kangaskhan is extremely protective of its child. If you so much as threaten it, you'll have to deal with a 7 foot tall kangaroo-dinosaur hybrid.
This trait can extend to other Pokémon as well, such as Gardevoir.
What spurs Samus Aran to action in Super Metroid is the Space Pirates stealing the baby Metroid that thinks she is its mother. Here, though, it's less motherly affection and more that letting the Space Pirates get their hands on a Metroid is an unspeakably bad idea.
The Queen Metroid's reason for attacking Samus in Metroid II: Return of Samus was also implied to be of this trope, as an egg was seen behind the Queen, and she also spawned several Metroids to take care of Samus in case she intended to kill the remaining hatchling. Other M also reinforces this theory, as evidenced by her attempt to shatter ice surrounding the various Metroids if frozen to reawaken them.
When Eyvel from Fire Emblem: Thracia 776 first came across a little Mareeta at a slave market, she slaughtered all the traders and guards and promptly adopted the small girl as her own. (If only her in-game stats were better.) Her raging maternal instincts are likely a result of the children she lost after getting amnesia. Her epilogue has her recovering her memories and reuniting with them.
Basically the reason why Cuan's mother Alfiona told Finn to ask Princess Raquesis for help to protect Leif in the back-story of Leonster's fall. Lachesis is a Master Knight, that is canonically an extremely skilled fighter able to use nearly any weapon, and would have her very young daughter Nanna to protect (not to mention, Nanna is all but stated to be Finn's daughter) , making her even stronger in the opinion of Lady Alfiona. And it mostly worked, with Raquesis as quite the Parental Substitute for Leif before disappearing in her way to retrieve her son Delmud.
Averted and then played straight in Final Fantasy VI. During the first Humbaba fight, Terra attempts to stand up to the demon to protect the orphans of Mobliz, having become their surrogate mother. However, the emotional turmoil she's gone through has robbed her of her Esper powers, and Humbaba easily defeats her. When the party returns, Humbaba attacks again. Unfortunately for Humbaba, he didn't realize that not only were two of the (teenaged) orphans going to have a baby together, but also that the annoying party attacking him was Terra's True Companions. The ensuing fight has Terra in Esper Modefor the entire battle.
Hope's mother, Nora Estheim, from Final Fantasy XIII, Unfortunately, she dies mere moments later. But it's the thought that counts.
Nora: "Moms are tough."
Lightning gets a Promotion to Parent for her younger sister, who gets kidnapped and turned into a L'Cie. Lightning is a Super Soldier military woman who blows up a train, decimates a military unit, hijacks equipment to break into an ancient temple, and takes on a god-like being to rescue her in the first hour of the game.
Lightning starts out dismissive of Hope and impatient with his neediness born from the trauma of the above spoiler. In a fit of frustration she tries to abandon him. This triggers the appearance of her Eidolon Odin, who tries to strike down Hope. At the moment of truth, Lightning defends Hope from Odin, passing the challenge all L'Cie must face. From that point on, Lightning acts as a Mama Bear to Hope as well, though Hope eventually outgrows the need for one thanks to his own Character Development.
Cosmos of Dissidia: Final Fantasy, who often acts as the Team Mom for her warriors qualifies. Especially when you take into account the fact that she deliberately allowed herself to be weakened enough to be killed by Chaos to give her warriors the power they'd need to survive her death and last long enough to defeat Chaos and escape the war.
Jade, the heroine of Beyond Good & Evil, operates a friendly shelter for war orphans, whom she views as her "children." In the opening sequence of the game, a band of evil aliens attempt to kidnap the children from the shelter. Naturally, very bad things happen to said aliens. Also, near the end of the game, all of the children get kidnapped. After working her way through a Heroic BSOD, her resolve goes Up to Eleven, and not a force in the galaxy will stop her from fighting to get her kids back.
Lauren Winter from Heavy Rain couldn't save her son from the Origami Killer, but swears on her son's grave to kill the man who did. And in one ending, she does just that.
Juno in Soul Nomad & the World Eaters is very devoted to her adopted son Penn — considerably more so than the child's biological parent. In the Demon Path this devotion takes on a whole new level of fanaticism when Juno demands Penn's return after he joins team evil, upon which Revya states that they didn't really want him in the first place.
Juno:"What...? You kidnap him, and you don't even want him? What's wrong with him? He's cute! Everyone should want to kidnap him! You will pay for not wanting to kidnap him!"
In World of Warcraft, there is a new talent in the druid class' Feral tree called "Protector of the Pack." It increases your attack power and decreases the amount of damage you take for every member in your party. For those who've never played, druids in bear-form are essentially meat shields.
And Alexstrasza: "Nekrosss...You had them ssslay my children! My children!"
With the new Cataclysm expansion, Beauty, the core hound boss, along with her 4 pups, of the new dungeon Blackrock Caverns will one by one 1-hit your entire party if the runt of the litter, creatively named Runty, ever dies.
It's kind off weird that killing any of the other puppies doesn't even affect the ferocious mother.
In the Worgen starting zone, there is a small series of quests involving a Grandma Wahl. One such quests asks you to find her lost cat before the evacuation. Once you find him, you are ambushed by a Forsaken, saying the cat would make good bait. Just as you engage him, Grandma, who we now learn is also a Worgen runs up to save her cat. "You do not mess with my kitty you son of a mongrel!"
In the 7th Touhou game, Perfect Cherry Blossom, the player encounters Chen as the stage 2 boss. When the player encounters and defeats Chen a second time on the Extra Stage, they are soon greeted by Chen's master, Ran Yakumo, who is not at all pleased with the protagonist's treatment of Chen. Cue the game's difficult Bonus Boss battle. From this scene, many fans have interpreted Ran and Chen's relationship as being like mother and daughter.
Melissa from Siren: Blood Curse. And lord help you if you have Bella and she's in her Maggot Shibito form. "BELLAAAAA!! MY BABYYY!!!"
Sadly, this gets turned into a weapon against Sophie later on in the series. In Soulcalibur III, Tira marks Sophitia's children Pyrrha and Patroklos as possible hosts for Soul Edge. She then makes good on her promise by kidnapping Pyrrha in IV, strong-arming Sophitia into working for Nightmare lest she want to endanger her firstborn. If that wasn't enough, backstory materials for SCV somberly reveal that Sophitia ended up sacrificing herself by removing the Soul Edge shard embedded near her heart (from when she shattered the lesser of the Soul Edge swords wielded by Cervantes all the way back in Soul Edge) to save the life of Pyrrha.
Resident Evil 2. If you're a child hopelessly lost in a zombie- and monster-infested setting, all you need to do is find a safe spot to hide and hope that Claire Redfield is in the area.
Bayonetta is this to a little girl named Cereza. This causes a Stable Time Loop, as Cereza is actually Bayonetta as a child, and Bayonetta became what she was by presumably imitating her "mother".
Arl Eamon's wife Lady Isolde of Dragon Age: Originsgoes to some pretty extreme lengths to protect her son Connor. To hide Connor's magical potential she blatantly goes against the laws of the Chantry and hires Jowan, an apostate Blood Mage, to teach Connor just enough magic to be able to hide his abilities from others. This leads to disaster, to put it lightly. Later, after Connor has been possessed, Isolde lures Bann Teagan to the castle at "Connor"'s request. At the end, unless you Take a Third Option, Isolde will either allow herself to be sacrificed in a Blood Magic ritual to save Connor, or ask the Grey Warden to allow her to peacefully kill Connor herself to end his suffering.
A weird, weird example can be found in the joined games of The Legend of Zelda Oracle games. The sister witches Koume and Kotake will do anything for their adopted son Ganondorf. They are the secret Big Bad of both games, the goal of which can only be seen when the games are linked up; they want to sacrifice Princess Zelda as part of a ritual to revive Ganondorf, and when Link screws that up for them, they sacrifice themselves instead.
In BioShock, once Brigid Tenenbaum's maternal instinct kicks in, she spends her time rounding up and saving the Little Sisters. Then after she finally escapes Rapture, she goes back for the sisters that were left in the city.
In Bioshock Infinite Elizabeth is not happy when children are in danger. When it is clear that Daisy Fitzroy intends to kill a Jerimiah Fink's son, Elizabeth stabs her in the back with a pair of scissors.
In Baldur's Gate II: Throne of Baal, the witch who raised Yaga-Shura and taught him how to render himself invulnerable by turning his heart into a Soul Jar initially asks you to retrieve his and her hearts so she can render him mortal since he betrayed her and she wants revenge. Immediately after the ritual is complete, her restored heart causes her feelings of maternal love to return. Realizing that your party will try to kill Yaga-Shura, she attacks your party despite being hopelessly outmatched.
Angry Birds. Those pigs really should not have messed with the eggs.
In Psychonauts, one could interpret Milla in this way—a Badass psychic secret agent who also loves kids, she is not happy when she's revived from Oleander stealing her, Sasha and their students' brains. This interpretation becomes more clear when you use Clairvoyance on her (she sees her students as babies) and when you find her back story (which reveals trauma from the Orphanage of Love she worked at burning to the ground).
Mary Barrows (or Burroughs) from Clock Tower is a villainous example: She is the mother of two extremely disturbed children, Bobby and Dan (their conception is heavily implied to be the result of occult work), and is very protective of them, to the extent that she is perfectly willing to kill Jennifer and three other orphans she adopted just to prevent them from killing the boys, and also intended to murder Jennifer in one of the endings specifically because the latter killed Bobby and Dan, but ended up being killed herself.
Palutena in Kid Icarus: Uprising shows signs of being one toward Pit, especially in later chapters of the game. By the end of Chapter 21, when Pit saves Dark Pit from Chaos Kin, his wings are burned as a result. Palutena is in a state of shock over what's happened, given that Pit might die. What does she do? Have Dark Pit go to the spring of time and dip Pit's wings into the water and bring him back to life. In Viridi's own words, Palutena is willing to go down into the Underworld and cheat death just to save her precious Captain (who she might see as a son, depending on interpretation).
Lei-Lei/Hsien-Ko and Ling-Ling/Mei-Ling's Action Mom in the Darkstalkers series, several times. First, she died in an Heroic Sacrifice to save the girls from Pyron, which is the reason why Hsien-Ko and Mei-Ling turned themselves into a Chinese Vampire-inspired magical being and her sealing ward respectively. Then, in the second game as the girls die to revive her, she uses her powers to help them being reincarnated into normal kids. And in the third game, when the reborn twins are forcibly turned back into magical beings and engulfed by the darkness, she again rescues them and sends them back to their normal lives.
This Team Fortress 2 comic "A Cold Day in Hell" features a literal example. After Scout, Soldier, and Pyro kill three bears, the Heavy states that those bears were babies. Scout dismisses his statement, thinking that "everything's a baby to [him]", but the Heavy's words ring true; those bears were babies of an angered mother bear.