Dead or Alive: After leaving her village to take revenge on Raidou for crippling Hayate when no one else would, this seems to be Kasumi's fate thus far, in addition to being marked for death by the Mugen Tenshin Clan. However, the endings of Dimensions and DOA5, the two most recent games in the franchise, have called this into question.
Secret of Mana for the SNES kicked off the plot with this, when The Hero is kicked out of his home village for removing a rusty sword from a stone, thus drawing monsters to it. In order to Set Right What Once Went Wrong, he has to find a way to unlock the sword's true potential.
With a little glitching, he can go home again, but he can't get out.
Also, in Seiken Densetsu 3, if you have Duran in your party and try to enter his house in Forcena, he will say that he can't return home until he has killed Koren, and the party will be unable to enter the house. Even after you kill Koren you still can't enter his house!
In Luminous Arc 3Sara and Sion was supposed to have liver hundred year ago but because of wrong experiment that caused them to be in the present era. While Sion adapted her live Sara still want to return to the past. In the end both of them give up and continue their life with Sara become principal of Urgard and Sion become famous actress and depend on who you choose, the main reason is they want to be with Levi.
For most of Tales of Symphonia, Lloyd is exiled from his hometown due to a petulant proclamation by an arrogant mayor who scapegoats him for the town's problems.
Averted toward the end of the first disc when The characters must decide which side they stay on when they separate the worlds. Ultimately, this is ruled out as a solution.
Made stranger by the fact that not even an hour later he is in the company of a knight and a princess, both of whom could have easily stood up for his character and cleared his name.
Less strange when you realize he was exiled for using forbidden Lost Technology (even if, in the original, you choose not to; The Remake changes things so that the gun is the only weapon Rudy has.)
Half-Life: Opposing Force's Adrian Shephard can't go home again because he was trapped by the G-man in an alternate dimension to preserve him. All in the name of "discretion". Which ultimately is made more depressing by the fact that Earth is now a Crap Sack World under the jackboots of the Combine.
Final Fantasy X: Tidus spends most of the game looking forward to returning to Zanarkand, which he discovers is pretty impossible seeing that it's been in ruins for the past thousand years and wasn't even really his Zanarkand anyway because he had been living in a literal dreamworld.
Final Fantasy VII has it too. Cloud and Tifa can never have their home town back because it was burned to the ground by Sephiroth. Although the town is rebuilt by Shinra and stocked with actors to cover up the event later in the game, the implication is still the same.
In Final Fantasy IX, this happens to a lot of the characters due to the massive property damage over the course of the game, but special mention to the Terrans (including Zidane), whose home planet gets blown up, and the summoners Eiko and Garnet, whose village was nuked in the backstory.
Might be the fate of the crew of The Spirit Of Fire From Halo Wars
Rath from Fire Emblem 7 was outcast from the Kutolah tribe at a very young age, due to a prophecy that said he'd have a great future if he saw the world on his own. In his solo ending, he returns to the tribe after the end and his tribesmen welcome him back warmly; in his paired ending with Lyn, Rath comes back alone but some time later Lyn joins him and they have a daughter, Sue.
Suikoden I has you being branded as traitors to the Empire, and being forced to flee from Gregminster. After taking up arms against them and fighting their forces back for the entire game, you finally return to and invade Gregminster at the very end of the game.
In Suikoden II, you become branded as traitor's to your home country, and upon first returning to Kyaro, are arrested. After being rescued from your imminent execution, you're unable to return there until quite late in the game, around the time when you lay siege to the country's capital.
In Suikoden III, Hugo experiences this early on when the Zexen Knights invade and burn down Karaya Village. Also implied for Watari, whose ninja clan is set to kill him for abandoning them.
Averted in Suikoden IV. Though you are scapegoated and exiled for a crime you didn't commit early in the game, you do eventually come back. Given the circumstances of your return, it's not a very happy occasion. And it's not really your homeland anyway. Ironically your original home is one of the first places you visit after you are exiled.
In Suikoden V, you are forced to leave home when the palace is attacked and the hero's parents are killed, and are unable to return to Sol Falena until winning every battle in the game.
InuYasha: Secret of the Cursed Mask (which has little to do with a cursed mask) the main character is yanked out of his or her time and can't return. Kagome's normal method of using the well is established early on to not work for the protagonist.
In Terranigma, Ark is literally unable to return to his home in the underworld, as the portal in the ground closes after he goes to the surface. The game plays with this idea, allowing him to purchase a home in the surface world, but it only serves to heighten a sense of homesickness which the character comments on in one of the climaxes. In the end, he is finally allowed to return home... only for him to seal it away by necessity, since his home was the domain of Dark Gaia.
Knights of the Old Republic: Jedi certainly aren't supposed to go home. Or have any contact with their family ever again, for that matter.
Carth Onasi's homeworld Telos was glassed by the Sith in the backstory.
A similar fate is inflicted on Juhani's and Mission's adopted homeworld Taris during the game.
Zaalbar was exiled from his homeworld for attacking his brother with his claws, a massive taboo among the Wookiees.
In Mass Effect, all three of Shepard's backgrounds ensure that they can never go home again: if you choose Earthborn, Shepard is an orphan who grew up on the streets; if you choose Colonist, Shepard's parents were killed and the colony razed in a batarian raid; if you choose Spaceborn, Shepard has a family, but grew up on multiple space stations and colonies as they moved around with the military.
Played with for Colonist Shepard in the third game. S/he mentions that they rebuilt Mindoir, but it wasn't the same afterwards, with his/her tone of voice indicating that it also contains too many painful memories. Shepard can go home again, s/he just doesn't want to.
In Mass Effect 2, Miranda parted from her father on rather bad terms.
Miranda: Shots were fired.
Also in Mass Effect 2, Tali can end up exiled from her fleet during her loyalty mission.
In Mass Effect 3, Shepherd has to leave Earth due to the Reaper invasion, although that's only their "home" in one of the three possible backgrounds.
In Dragon Age: Origins, the trope is both played straight and averted for the six origins. Five of the six are not only able to return home, but have to return there in the course of playing the game. The Mage returns to the Circle of Magi during the "Broken Circle" quest; the City Elf helps drive slavers out of the Alienage where they grew up; the Dalish Elf returns to the Brecilian Forest to recruit members of another elven clan to help fight the darkspawn; and the Dwarf Noble and Dwarf Commoner both go back to Orzammar to settle the question of who becomes king. The trope is played painfully straight, however, for the Human Noble, whose ancestral home - Castle Cousland - is never seen again after the origin is completed, which is probably for the best since it's littered with the corpses of everyone else who lived there.
Sten also has this issue, as he cannot return home to give his report because his sword was lost. As he explains it, the sword was forged for his hands, and he "was to die wielding it." If he returned home without it, he would be slain on-sight by the Qunari border guards as it would mean he was 'without his soul'.
Zevran has quit his role as an Antivan Crow, and thus if he ever goes anywhere near Antiva again they'll probably have him assassinated.
Leliana is in Ferelden after a botched mission left her with treason charges in Orlais.
In Dragon Age II, Hawke's Doomed Hometown of Lothering is destroyed by the Darkspawn horde at the beginning of the game. It's eventually rebuilt at some point over the next seven years, but by that time Hawke is pretty enmeshed in Kirkwall's problems and has begun to set in roots. However, Hawke's mother comments that Hawke and his/her siblings "are Fereldan to your toes," and dialogue in one minor quest can have Hawke state that despite their role as Champion of Kirkwall, s/he will always consider Ferelden to be their home.
Invoked by Aveline when discussing her own reticence to return to post-Blight Ferelden in Act One, much like Hawke's family.
Aveline: You can't go home again. That's supposed to be about maturity. It's not the same if you don't have the option.
Fenris doesn't want to go home after all the Magisters of Tevinter did to him. Merrill's character arc begins with her leaving her clan to live in the Kirkwall alienage - and the least bloody ending still leaves her exiled forever.
The shipwrecked qunari platoon spend roughly four years "waiting for a second ship", when in reality they're stuck in Kirkwall until their Arishok recovers their sacred text and the one who stole it. As Kirkwall is almost the perfect opposite of ordered qunari society, this really gets to the Arishok.
In Ōkami, your Ninja Butterfly Issun ran away from home rather than become a celestial envoy and refuses to accompany you when you have a chance to go to his hometown. Also, the celestial beings murdered by Yami can't ever go back to the Celestial Plane.
In 3 in Three, the main character spends most of the plot trying to get back to the spreadsheet she lived in, only to discover in the end that she doesn't really belong there anymore.
In Baldur's Gate, Gorion's influence was pretty much the only reason Ulraunt tolerated your presence in Candlekeep. When he dies, the fortress becomes as off limits to you as it is to the rest of the world. The sequel touches on this a few times as well: as time passes, you become a big fish in a very small pond — even if they did let you go back home, could you ever be content there?
You can (and in fact have to) go back to Candlekeep some time after Gorion's death while following the conspiracy you have been embroiled in all this time, only to discover that nearly everyone you knew there was killed and replaced by doppelgangers.
In the Warcraft universe, those High Elves who remain loyal to the Alliance, after most of their brethren join the Blood Elves who defect to the Horde. Also those humans and elves who fled the kingdom of Lordaeron when it fell to the undead.
Recent developments in World of Warcraft: The blood elves of formerly-neutral Dalaran have all been arrested, kicked out, or killed as the city-state joins the Alliance. Also, Vol'jin, leader of the Horde's trolls, lived through an assassination attempt from one of Garrosh's soldiers and is now hiding out in Pandaria while the Horde believes him dead.
In Otherspace, the universe that houses our solar system began to break apart due to a massive war between titanic forces, forcing the players to make the journey to a new universe and start over there.
In X3: Reunion, three games and several dozen years later, the Solar System is reconnected to the X-Universe's Portal Network at the end of the main plot. By this time, Kyle Brennan has a grown son in the X-Universe, is a war hero, and is the head of a multibillion-credit company. At best, he'd likely be a Stranger in a Familiar Land.
The X-Encyclopedia included in the X-Superbox series collection states that he did return to Earth after Reunion, and began working as a political activist in favor of closer diplomatic relations between the Terrans and the Community of Planets. It didn't help much; Earth soon became embroiled in a Space Cold War with the Commonwealth, which erupted into a hot war about a decade later.
Super Mario Galaxy had a subplot which demonstrated that remaining in space too long will result in you finding all of your friends on Earth now long dead.
At the beginning of Fallout 3, the Lone Wanderer is living with his father, James, in the underground shelter Vault 101. However, when James leaves the Vault, the paranoid Vault Overseer tries to have the Wanderer killed, forcing him to flee into the Wasteland to find his father. Later, the Wanderer returns to the Vault to find that it's inhabitants are embroiled in a civil war over whether or not to keep the Vault locked down. If the Wanderer finds a peaceful solution, his childhood friend Amata becomes the new Overseer. However, as she explains, a lot of people still blame him for everything that went wrong. For the sake of peace in the Vault, the Wanderer is forced to leave again, this time for good.
The original Fallout ends with the Vault Dweller being banished from his Vault, due to having been radically changed by his experiences in the wastes and possible hero worship amongst the Vault's younger dwellers causing them to leave en masse.
Played with almost to the point of Mind Screw in Neverwinter Nights 2. The Knight-Captain'sDoomed Hometown actually fights off the attack that normally destroys it in that trope, with only four villagers (a Guest Star Party Member and three militia redshirts) confirmed dead. About two-thirds of the way through the plot, the village actually is destroyed by the Big Bad, but most of the villagers survive and, in the good ending, return to rebuild. Mask of the Betrayer takes the tack of moving the Knight-Captain to the other side of the continent. In two of the Multiple Endings, s/he gets to go home and potentially get married there. Another two endings play it straight by either having the Knight-Captain stay on the Fugue Plane permanently to bind the Spirit-eater there, or having him/her embrace their hunger and go on a rampage through the universe eating every spirit in sight.
The Exiles of WildStar are an entire faction of this, depressingly enough.
The Exile Humans were chased off of their homeworld of Cassus when The Empire instituted oppressive policies and cracked down on any and all dissenters.
The Granok fought against the Dominion, turning the tide of the war by stealing their tech and chasing them off. Their leaders, however, believed them to have betrayed their ideals (said leaders were ready to accept death) and banished them.
The Aurin were innocents who the Dominion targeted when they learned they were helping the Exiles, harvesting their planet's natural resources until it was laid barren.
The Mordesh used to be allies of the Dominion until a medical breakthrough they created backfired horribly, turning the race into "space zombies". When the Dominion abandoned them, they turned to the Exiles for help.
In the first The Sims game, if a child fails school, s/he will be sent to military school and will never be seen or heard from again.
Same thing for couples who break up. One of them will leave the house and will never be seen or heard from again.
In the Ace Attorney series, Misty Fey was forced into hiding after she was publicly disgraced after the DL-6 Incident. Even after her name was cleared, in the first game, she isn't able to return to her old life.
In Little Inferno, the Arc Words are "You can go as far as you like, but you can't ever go back". And when your home burns down, that's it - it's time for you to to walk away, go on an adventure, and find something to do in the world more worthwhile than burning things in a fireplace.