In Mobile Suit Gundam, Amuro Ray goes to visit his mother on Earth, and ends shooting the Zeon patrol searching for him. His mother is dismayed by how much the war has changed her little boy, and they part less than amicably.
This happens at the end of Season 2 of Monster Rancher, where Genki's sudden return to Earth after a good year or so in another world is portrayed to be as devastating as you would expect.
Ayato in RahXephon, at several points in the story.
Depicted in Inuyasha to some degree. Kagome has three friends from her school, and we see how she has less and less in common with them the once or twice per season she returns home; they're thinking of tests and cute boys, while her circumstances have her outgrowing normal high-school concerns. When she talks about her romantic troubles but leaves out the details, they think he's just hung up on his ex, while the truth is more like "his dead previous fiancee isn't dead, and we don't know which side she's on or what her complicated long-term game is, as if an Artifact of Doom-wielder who only gets more unkillable every week wasn't enough."
Part of the Deconstruction of Homura's ability to go back in time to Set Right What Once Went Wrong in Puella Magi Madoka Magica. The multiple attempts to change Madoka's fate end up changing Homura's personality from a Shrinking VioletMeganekko to a cold Shell ShockedAloof Dark HairedMagical Girl who grows more and more distant from the other four girls with each repetition of the timeline because of what she knows and what they don't. The original vulernable Moemura is kept buried deep inside, only evident in select instances such as in Episode 10, when she tearfully laments to Madoka that while to her Homura was this mysterious transfer student whom she had only known for a few weeks, to Homura Madoka was everything because she had given up so much for her sake.
In the Comic In A Comic of Watchmen, the survivor of a pirate raid desperately attempts to return home to warn of the pirates' imminent arrival. He clearly goes insane in his certainty he will be too late, and fails to recognize his own family on return.
One of the actors in The Movie compared the superheroes' situation to 'War veterans trying to fit in with society'.
Samaritan from Astro City is a particularly extreme example - he was born in a desolate future where humanity was about to die out, and was sent back in time to our era to change history. He eventually ended up in a fight with a villain who we assume had some sort of time-related powers, which got him sent back to his own time. He discovered that he'd succeeded in his mission, and that the future was now one where humanity was thriving, but the changes he'd made were so extensive that he'd become a temporal anomaly - the rest of his family were never born, and what was his home had become a taco stand.
In a later story that tells of Samaritan's archenemy Infidel, the immortal Infidel traveled forward in time and built an empire in Samaritan's old world, only to be shocked and appalled at the ignominy when he finds that his home (which had been coincidentally built on the wreckage of Samaritan's) had also become the same taco stand.
The DC Comics villain Superboy-Prime spent most of his existence trying to return to his home universe where all these annoying super-beings only existed in comic books. He finally succeeded at the end of the Final CrisisMega Crossover. But when he got home, he discovered that his family and girlfriend had been following his "adventures" in the comics - all the atrocities he had committed, the tortures, the mutilations, and the at-least-eleven-digit body count he had racked up - and considered him a monster.
The situation occurs in The Life and Times of Scrooge McDuck by Don Rosa. Scrooge leaves Scotland as a 13-year-old and briefly visits home when 18. In 1902, a 35-year-old Scrooge has earned a small fortune and attempts to resettle in Scotland. Having spend most of his life in the United States, South Africa, Australia and Canada, Scrooge has problems being accepted by traditional Scottish villagers. Soon Scrooge decides to return to the United States, this time taking his two sisters with him.
In the "Threeboot" version of the Legion of Super-Heroes, Triplicate Girl comes from a planet populated entirely by duplicates of herself. At one point, she tried to go back, only to find that the selves that had remained on the planet were now afraid of her, because her adventures with the Legion had changed her so much that she was no longer identical to them and they now saw her as an outsider.
Happens to Travis Morgan whenever he returns to Earth in The Warlord. These visits just reinforce Morgan's belief that the Lost World of Skataris is where he truly belongs.
Both the non-canonical Ghost In the Machine and the Canon comic Tron: Betrayal imply this happened to Flynn (who behaved erratically and vanished in both continuities).
Jason Aaron's Punisher MAX story arc "Frank" details Frank Castle's experiences with this back during the period between his return from Vietnam and the death of his family. He struggled to be a normal family man again, but the whole time he desperately craved a return to war and violence in general. Parallels are drawn between this period in his past and the present, where he's in prison.
Captain America is depicted this way in modern incarnations (especially his Ultimate counterpart). He was frozen in a block of ice during WWII and was originally thawed out in the 1960s. As comics have continued however, the gap in between when he was frozen and thawed out has grown larger, spanning decades and decades, making Cap feel even more out-of-place with the current world and, in Ultimate Cap's case, its sensibilities. Regardless, he's still looked up to as the pinnacle of heroism in the Marvel Universe, and an example for all to follow.
This also happens to Cap whenever he time-travels back to the 1940s. The casual racism and sexism of the era makes him feel entirely out of place.
Nova: Richard Rider had difficulties on returning to Earth after that Annihilation business. It didn't help that he'd returned right after Civil War, and is disturbed by the news of everything that's happened (including that his former girlfriend died right at the beginning of the event). After an attack by a supervillain, followed by the Thunderbolts when he arrests said supervillain, where he's treated as the villain just because he's there, Rich finally decides to leave, announcing "I think the world's gone insane, and I want off". So, after one disturbing conversation with a psychologically damaged Speedball, he leaves.
In He Who Fights Monsters Tsukune comes home and realizes how much Yokai Academy has changed him when his mother comments on his constant tenseness and when he almost kills his old bully.
Near the end of Make A Wish Harry returns to England and finds out after removing his disguise as Mr. Black that he needs another disguise to hide all the changes he's gone through over his summer.
In Pony POV Series, Shining Armor, Minuette, and Cadence end up in a downplayed version of this trope after Makarov's demise triggers a Cosmic Retcon that erases him from history. They awaken in a new timeline where much has changed due to the Hoovet Empire having imploded on schedule and Makarov's changes to the timeline being undone, but retain their memories (due to being Immune to Fate, a Time Lord, and an Alicorn respectively). Downplayed, as they have new memories that help them adjust, but still takes some getting used to.
Cast Away: Chuck Noland comes home after years being stranded on an island to find that his friends had him declared dead and actually had a funeral, and his fiancee married another man.
Hamburger Hill: Sgt. Worchester monologue about his experience with anti-war activists became his motivation to do another tour in 'Nam.
In Apocalypse Now, Willard is in a very similar state and mentions how he couldn't adjust to life at home. Worse still, he's clearly not satisfied with living in the Vietnam War, becomming even more of a stranger to it by the end.
A strange case in The Shawshank Redemption finds elderly parolee Brooks unable to fit in outside the walls of the prison in which he's spent the better part of his life. Spotlighted when he writes to his friends on the inside, commenting on how he saw a single automobile when he was a boy...and now they're all over the place.
In Sniper, Thomas Beckett tells Richard Miller that he's going to retire from the Marine Corps and return home, then details all the things he's going to do once he gets there only to find out from Miller that most of the places he talks about don't exist any more.
The Hurt Locker. When Will James' tour in Iraq is finished, he's obviously out of place in his civilian life. The guy even has a hard time grocery shopping.The movie ends with him going back to war, walking downrange in the bomb suit with a satisfied look on his face.
In The Color Purple after a character returns from prison after so many years, she weeps after commenting that she doesn't know any of her friends or family anymore.
In the French film I Have Loved You So Long, a woman is let out of prison after serving 15 years for murder of her suffering terminally ill child. When she is released, her father is dead, her mother is senile, her friends have cut off all ties to her, and her baby sister has almost no memories of her whatsoever. Despite this, the woman's sister takes her into her home and tries to become a normal family again.
Gives The Last Unicorn a very Bittersweet Ending. The eponymous unicorn can't stay among humans, since so few are pure enough to recognize her and treat her as an intelligent being deserves, but her time as a human has allowed her to know love and hurt and joy, things normal unicorns never experience, so she'll never again fit in among the eternally unchanging, emotionless creatures that were once her own kind. Still, she thanks Schmendrick for the experience, with the claim that if she had to do it again she would. Also in the original novel.
In Madagascar 3: Europe's Most Wanted, Alex, Marty, Gloria, and Melman finally complete The Homeward Journey. Unfortunately, their adventures throughout the series made them unfit at the Central Park Zoo. To make things worse, they're apprehended and trapped there with increased security measures, and the animal control officer who captured them still wants them dead. Fortunately, their friends come to their rescue, and in the end Alex and the gang decide they belong in a touring circus.
In Get Carter, Jack Carter returns to his home town of Newcastle to investigate the murder of his brother. Since he left, he's become a big-shot London Gangster, so his relationship with the town is quite different.
In the German film Stalingrad, one Landser relates how he came back for R&R and just felt like he couldn't live a life away from the front anymore. He tells his comrades that he just asked that his wife be told he fell in combat so he would not have to visit her at home and she wouldn't have to worry about him anymore.
In My Fair Lady, after she's finally fed up with Professor Henry Higgins, Eliza returns to the old neighborhood after her blossoming into a lady, but no one recognizes her.
In Tough Guys, Burt Lancaster and Kirk Douglas play convicted train robbers Harry Doyle and Archie Long who are released after serving 30 years in prison and they're shocked by how much the world has changed while they were in prison.
The Lord of the Rings has the hobbits return to the Shire and share a drink at their local watering hole, looking completely alienated and distanced from the other hobbits.
In Cinema Paradiso, when Toto returns home from his conscripted service in the army, he has found that his home town is very different. Alfredo advises him to leave forever and he does, until Alfredo dies.
In The Student Prince in Old Heidelberg, Prince Karl Heinrich goes back to his old college after becoming King and finds out that nothing is the same anymore. The students no longer come to the beer hall where he used to hang out and have fun, and his old frat buddies now behave towards him in a stiffly correct manner, now that he's king.
In American History X, the protagonist gets this feeling after returning home from prison. He is a changed person who does no longer fit in with his former skinhead gang and their racists ideology.
At first this seems to be part of the Central Theme of The World's End: five friends return to the town where they grew up after being estranged from it for many years, and find it uncomfortable and hostile. They assume this trope is at hand until by accident they find that, in fact, most of the townsfolk have been replaced by alien robots.
Rachel in #48 The Return. She has an internal monologue about how she feels isolated and apart even in a crowded school hallway.
Jake, who can't relate to anyone after the war because they don't know what he's been through.
Also, Tobias, as he's now a hawk, and since Rachel is dead, he has no more connection to humanity.
And Ax. The things he's learned on Earth - the willingness to justify your actions to your subordinates, the acceptance of vecols as members of society - cause him to be seen as strange to other Andalites. Although, by this time, he's enough of a legendary war hero to get away with it.
Thomas Wolfe's You Can't Go Home Again has elements of both that trope and this one.
Elijah Baley at the end of Isaac Asimov's second Robot novel, The Naked Sun. Partially undermined at the beginning of the third novel, as Baley realizes he's not as foreign to the Cities as he had first believed.
He'd spent his entire life there, but his son (and many of the next generation of Earthers) will be.
Bill Bryson's I'm A Stranger Here Myself (called Notes from a Big Country outside the U.S.) describes his experiences living in America after 25 years in the U.K. It includes such anecdotes as walking into a hardware store looking for Spackle, and realizing that he had never been a homeowner in his native country before and didn't know what the stuff he needed was called:
"Hi, I'm looking for the stuff you use to fill dents in walls. My wife's people call it Polyfilla."
To some extent, Kareen Koudelka returning to Barrayar in A Civil Campaign after her year on Beta Colony.
In David Eddings' Castle of Wizardry, the fourth book of The Belgariad, the group visits the home farm of The Hero, and he realizes that he's changed so much that he can't really expect to return there after their quest is completed.
This happens a lot in the works of William Faulkner, but it's most prevalent in Flags in the Dust, where Bayard has to deal with coming home from WWI when his twin brother...didn't.
Neil Gaiman's novels Neverwhere and Stardust. In the latter, the protagonist has changed to such a degree that several townspeople can't recognize him, and they treat him with great suspicion.
In Joe Haldeman's novel The Forever War, the main character, a soldier in the war, repeatedly deals with culture shock because, thanks to relativistic time dilation, time passes more quickly on Earth than it does for him. During the novel, the main character experiences four years, but centuries pass on Earth. Word of God says that the novel was inspired by the author's experience of fighting in the Vietnam War and then returning home.
Played to devastating effect with Mandella and Potter's return to Earth after their first tour of duty, during which thirty years have passed on Earth due to Time Dilation from Faster-Than-Light Travel. Mandella's father is dead; his mother is dying of cancer which The Government's socialized medicine system refuses to treat because she is not worth it, and she has taken a lesbian lover. Potter's parents are forced out of their home for defying government regulations, and end up on an agricultural commune under assumed identities. They are killed while Mandella and Potter are staying with them by raiders looking for food. Needless to say, the two re-enlist in the Army and get off the planet.
At the end of Simon Hawke's first Time Wars novel, The Ivanhoe Gambit, Lucas is discharged from the Temporal Corps as a reward for his actions. He finds he doesn't fit into 27th Century civilian life any more, and re-enlists at the start of the second book, The Timekeeper Conspiracy.
Robert A. Heinlein uses this trope in some of his juvenile Science Fiction, when the protagonist has learned and grown from his (it's almost always a male) experiences, but the people back home have not.
Glory Road: A non-juvenile example. The protagonist eventually returns to his home world after his adventures, finds life too tame (in one example, Eternal Sexual Freedom is averted), and in effect signs up for another hitch.
Space Cadet: The protagonist, on returning from the Patrol'sBoarding School on leave, has it brought home forcefully to him that his family is deeply ignorant of the realities of space travel and the Patrol, and that they don't want to change any of their ideas.
Tunnel in the Sky: The protagonist's parents became Human Popsicles not long after he left for his final exam in Survival (a prerequisite for all of the professions connected with space exploration and colonization), because his father had an illness that just outside the current medical state-of-the-art's ability to cure. When he finally comes home some years later (the exam went bad in a big way), his parents can't quite wrap their heads around the fact that he's legally of age. (He was just shy of it when he took the exam, for which he had to get his legal guardian's permission. Fortunately, his parents had already made his big sister his guardian in preparation for their entry into cryogenic stasis, and she was in favor, so signed permission.)
Homer's The Odyssey. In this case, a spell was actually placed on the land so that Odysseus wouldn't recognize his homeland until he asked someone where he was.
In Diana Wynne Jones's novel The Homeward Bounders, Jamie jumps to modern-day Earth after having walked the bounds for some years...and discovers that it's actually his own homeworld, just a hundred years on, and the boy he's made friends with is actually his own great-nephew. Heck, Him deciding that modern day London wasn't Home anymore was a major plot point.
The short story The Long Night of Waiting: Two nineteenth century kids were accidentally swept into Another Dimension through a Cool Gate. They returned to find that roughly ten years had passed for every day they spent on the other side, and it was now the late twentieth century. They went back through the Cool Gate, since it was closer to the life they were used to and they now had some friends there.
Android at Arms: Several important persons from various species and cultures awaken on a Prison Planet and learn that they have been kidnapped, and apparently kept as Human Popsicles and replaced with Ridiculously Human Robots. It is established right away, from the most recent dates each can remember, that for some of them many years have passed, and all of them were abducted in the midst of time-critical situations. The protagonist (one of the more recent abductees) returns home to find that years have passed, and that his double is now in charge.
Judgement on Janus: After recovering from the Green Sick, Ashla attempts to contact her beloved younger sister, but learns that the physiological and psychological changes wrought by the illness are such that her sister no longer recognizes her, and that she cannot see her old home as home anymore.
For that matter, Rip Van Winkle himself in the Washington Irving story of the same name.
A recurring theme in the works of K.J. Parker. Parker loves to deconstruct the "local boy comes home and makes good" cliche.
In The Lord of the Rings ending, this happens to all of the hobbits in varying degrees. Frodo has the most problems with the "happily ever after" part, although Pippin and Merry also have trouble with staying in the Shire for long, and in the end they spend their last years with Aragorn in Minas Tirith. Sam is the only one who seems to fully fit in again, but after his wife dies, he follows in Frodo's footsteps and sails away to the Undying Lands in the True West. Some fans believe Frodo had PTSD. Tolkien was a veteran of World War One.
For that matter, The Hobbit hints at the same problem for Bilbo, and the opening of The Lord of the Rings even more so. His experiences with the Dwarves and Smaug ensured he never quite fit in with the hobbits again, and when he abandoned the Ring, he left the Shire for good, living the rest of his life with the Elves. First in Rivendell, later in Valinor.
The Sebastion Barry World War One era novel A Long Long Way uses both the changed protagonist and changed home themes. The hero is an Irish soldier on the Western Front who returns on leave to find Ireland utterly altered by revolution.
Timothy Zahn's The Cobra Trilogy deals with a group of cybernetically-augmented soldiers who meet with trouble when the war is won and they try to go home (partly because the changes include unalterable reflex actions); the first installment was a story ironically entitled "When Jonny Comes Marching Home."
In All Quiet on the Western Front, written by World War One survivor Erich Maria Remarque (see the pattern here?), the main character Paul Baeumer visits his home to find that he actually longs for the front. In a letter to his mother, he writes that it "now feels like I am really returning home".
In The Demonata by Darren Shan, the second book ends with Kernel returning home...however, due to time running differently in the the Demonata's universe, his parents had accepted his and his magically-transformed not-in-any-way-a brother's deaths years ago, and in the end he leaves again.
Happens twice in Shan's first series. The first is when, in book eight, Darren returns to a city he met his first girlfriend in, but doesn't fit in (though it's implied that 1. the city isn't in the same country that Darren is from, due to the accents school students use 2. when he's going back to school, as a fifteen-year-old, when the last time he was in school was the age of twelve, i.e. fifteen years ago, he ends up looking like an idiot. Plus, being a vampire prince who has spent almost a decade doing vampire-y things probably hasn't helped him fit in to humanity well.
The second is, in book eleven, Darren goes to his own hometown, and sees his sister, and other people, and decides it's better to not get involved in the lives of his former family and friends. Still, that doesn't stop the villains...
Teppic in Pyramids, who finds it difficult getting used to the ways of Djelibeybi after being educated in Ankh-Morpork, and at one point refers to Ankh as "where I come from". In fact, he's the Trope Namer:
Teppic stared at him and thought "I am a stranger in a familiar land."
Comes up a number of times in the books. The oft-quote reply is "you can't cross the same river twice".
Ridcully: Why not? This is a bridge.
An early book mentions that wizards often relish the chance to go home again... and meet every bully who wronged them, and get some magical payback.
Brian from the Hatchet series, after being forced to survive in the woods decides the woods are better when he goes home.
Edmund Dantes spent nearly fifteen years locked away on a prison island. Even though the point of his ruse as The Count was that none of his targets would know who he was till their end, even Mercedes has trouble recognizing him at first glance. It doesn't take her long to see through it, but nobody else does.
Oz series: Ironically, Dorothy Gale fell to this trope. The longer she stayed in Oz, the harder it was to go back to Kansas. Eventually, instead of having to choose between Em and Henry in Kansas and the wonders of Oz, she brought Em and Henry to Oz, where Ozma set them up with a little patch of farmland in Munchkin Country.
Moonraker. James Bond experiences this while in posh club Blades, imagining that his work as a Professional Killer has somehow made him 'un-English' and that the other club members can perceive this.
Happens to Graystripe twice in the Warrior Cats series - once when he comes back to ThunderClan after having left to raise his kits in RiverClan (where their mother had lived), and once when he is captured by Twolegs and is thought to be dead for over a year. Both times, though, it eventually fades away.
Also happens to Hollyleaf, when she returns after a year of having been thought of as dead, and then is instantly revealed to her Clanmates as a murderer (though her family covers for her, claiming Ashfur attacked her.)
Geary himself is struggling to adjust to an Alliance that has spent the last 100 years fighting a seemingly endless war.
One of the In-Universe folktales from Watership Down, El-ahrairah and the Black Rabbit of Inle, El-ahrairah returns from his adventure to find that full generations of rabbits have come and gone since he left and no one is left in his warren who remembers him.
At least two occasions in the Star Wars Expanded Universe deal with Luke Skywalker going back to Tatooine and seeing his old friends. He can't go home and his closest friends, Biggs Darklighter and Janek Sunber, have left and died, but he has some others. However, he was always kind of strange, by their standards, and none of them ever want to get out into the galaxy - returning, he has even less in common with them than before.
In Rebel Force he has to confront the fact that they just aren't inclined to believe any of his stories - the 'Wormie' kid they always derided for being an unrealistically big dreamer doesn't impress them. Leia has to bully and berate them into helping him, and he sees that they're more willing to think of her as someone amazing than they are to think of him. By then it's really sunk in that they will never really like him, and he thinks she's amazing too, so he's content to sit back.
During Marvel Star Wars, while he's there one of his old friends sells him out and tells him out of guilt before he can be ambushed, then defensively says that he doesn't know what it's like, trying to make it on Tatooine.
Happens at the end of De Gouden Dolk (The Golden Dagger), an adventure novel by Thea Beckman. After spending years of fighting in the second crusade, protagonist Jiri Rambor finds life in his old village boring and uneventfull after his return.
In Lovecraft's story The Lurking Fear we learn about a man named Jan Martense, who after 6 years in the army and exploring the world did no longer fit in with his isolated and xenophobic family.
In Harry Turtledove's Homeward Bound, this happens to the Yeagers (Sam, Jonathan, and Karen) after the FTL-capable Commodore Perry brings them back to Earth 30 years after they depart on the Sleeper StarshipAdmiral Peary for Home. This is also the case for members of the Race who have spent any lengthy period on Earth, as the lizards are not used to change (their empire having remained largely unchanged for the past 50,000 years).
It's mentioned that members of the Race have a support group of sorts for those who have travelled the stars.
Margaret Hale from North and South, on returning to her hometown after an absence of three years.
This happens in the Strugatsky Brothers' Noon Universe with astronauts leaving on relativistic trips to other stars. One returning astronaut hooks up with a girl after coming back, who finds it weird that people used to cook for themselves instead of going out to eat every day. Nobody has a kitchen in their home anymore, apparently, although the astronaut orders an automated kitchen only to accidentally get his neighbor's washer/dryer.
In Mikhail Akhmanov and Christopher Nicholas Gilmore's Captain French, or the Quest for Paradise, the titular character's backstory involves feeling this way after his historic relativistic flight to Alpha Centauri back in the 21st century (the events of the novel take place 20,000 years later). The original mission plan was to survey the system and return to Earth with a detailed report. Instead, French chooses to send a brief report via radio and continue to other star systems before finally returning home. However, his wife and daughter are long-dead by that point (they would've been alive if he'd returned as planned), and everyone treats him as a hero. The success of the new drive system results in government-operated space programs shutting down and private enterprises taking over. French ends up a hero without a job or any family or friends he recognizes. He finally decides that enough is enough when his ship is about to be sold at an auction. He absconds with the ship and sets course for the first extrasolar colony, pioneering space trade.
In The Satanic Verses Saladin Chamcha experiences this on a brief visit to his home in Mumbai, having spent most of his life in England.
Live Action TV
30 Rock plays this for laughs when Tracy tries to make his act more current by going out among the people to try and reconnect with his roots.
'Tracy(in the middle of New York City): Does anybody want to be my friend?
Teal'c in Stargate SG-1, at times when he briefly returns to Chulak.
On Boardwalk Empire, Jimmy Darmody and Richard Harrow both return from the First World War and have trouble fitting in to peacetime life, both ending up in the bootlegging trade.
Sam Tyler in Life On Mars, who finds himself unable to readjust to life in the present, after waking up from his coma, to the point that he doesn't notice any pain when he cuts his hand open, and ends up committing suicide to return to the life he had in 1973.
The castaways of Gilligan's Island were returned to civilization in the 1978 reunion movie Rescue from Gilligan's Island. The Skipper, unable to get an insurance settlement unless the passengers of the "Minnow" attest that the shipwreck was not his fault, travels with Gilligan to visit everyone. They find that returning to normal life has not been easy for their friends. Ginger is upset that raunchy movies have replaced the glamorous ones from her time, the Professor's inventions have been created in his absence (and he's being pressured to spend all his time raising funds for the university), the Howells have moved beyond their wealthy society friends and Mary Ann has outgrown her fiance.
Rose Tyler from Doctor Whoafter the Doctor tricks her into going home to save her from certain death. Also his former companion Sarah-Jane Smith, who complains about how hard it was just waking up every day and knowing she'd never see the grandeur of space again.
It is even more prominent with Donna. It only took one adventure with the Doctor, maybe for about an hour, for her to get hooked. While she declines to become his companion, she soon regrets it and goes looking for him to see if the offer still stands.
This trope seems to be pretty widespread, as it's a recurring theme in the new series that you can't just go back to normal life like nothing had happened. However, this leaves the ex-companions as quite a Badass force in protecting the Earth when the Daleks return.
Odo in Star Trek: Deep Space Nine - spends years trying to find the race from whom he was parted as an infant, and then when he finally does find them, they're the enemy of everything he holds dear.
Also Worf who finds that his humorless dedication to honor and duty has little to do with how Klingons in the Empire conduct themselves.
In one episode, a man takes his bride-to-be back to his hometown, which is slightly different than he remembered it. No one recognizes him. Someone else is living in the family home. He finds out he's a robot.
In another episode, a man wakes up after a night of drinking. When the woman next to him wakes up, she has no idea who he is, although he insists he's her husband. He spends the rest of the episode trying to prove who he is. In the end, the wife wakes up and the role has been reversed. No one knows who she is.
When Adrian Monk gets re-instated with the SFPD he finds that just about nothing is familiar.
John in Farscape when they finally get back to Earth in season 4. It's a combination of the world changing (his father points out 9/11 as a reason why countries can't cooperate the way John wants) and John being a completely different person due to his travels. This is partly why he leaves with Moya again, the other part being that Earth is in danger if he's there (and even when he's not, it turns out).
Lucius Vorenus in Rome returns to his home and his family after being away for 7 years on military service. He found it difficult to re-adjust to civilian life while kept getting in conflict with his wife. Things got better for him, though not for long.
Once Upon a Time: Most of the characters either had fake lives in Storybrooke or were frozen but conscious in the Enchanted Forest. Aurora was in her Deep Sleep for the entire length of the curse, so she has no idea how to handle the new, curse-ravaged forest, and she doesn't have the extra twenty-eight years of experience like her (fellow fairytale) companions.
The pilot of Defiance starts with a boy looking up as the Votan ships are descending to Earth. Fast-forward 33 years to an After the End partially-terraformed Earth with humans and the Votan races attempting to coexist. The protagonist, Nolan, arrives to a town called Defiance built atop the ruins of St. Louis (the Arch is still there). The ending of the pilot reveals that Nolan was the boy, and he was born and raised in St. Louis.
The Charlie Daniels Band song "Still in Saigon" tells of a Shell-Shocked Veteran who has returned home from Vietnam, and has flashbacks to his Vietnam service triggered by otherwise ordinary events.
The Atlanta Rhythm Section's "Homesick" is about the "native son of a foreign land" who's "lost in yesterday".
Paul Williams knows that this is what he would be in "Where Do I Go From Here":
''If I knew the way I'd go back home But the countryside has changed so much I'd surely end up lost
Half remembering names and faces
So far in the past
On the other side of bridges that were burned once they were crossed''
In "The House That Built Me" by Miranda Lambert has the narrator has come back to her childhood home in order to find herself, but the home itself is now owned by someone else. She asks the woman living there if she can come inside and relive some memories.
Comes up in a lot of songs by Bruce Springsteen, particularly "Long Walk Home".
Keane's "The Boys" (ironically on the album titled Strangeland) nearly states it word for word:
A major theme in the Underground roleplaying game from Mayfair Games. A Player Character begins as he's discharged from service as a genetically enhanced warrior conditioned to think of himself like an ultraviolent superhero, into a decaying ruins of American culture with civilians who fear and hate them and a corrupt and totalitarian government (an intentional reference to the state of Vietnam veterans coming home after the Vietnam War).
A serious problem for the Lost who are always changed by their time in Arcadia, and often find that earth has changed in their absence.
The original Fallout. Though perhaps in this case, it's not so much the Vault Dweller himself that has the problem, it's the Overseer telling him he could inspire some of the younger Vault dwellers to leave themselves, so the Player Character has to leave for the good of the community. You are, thankfully, given the option to shoot him in the face at that point.
Lampshaded in the sequel, Fallout 3, where Girl Next Door and possibly High School Sweetheart Amata calls the Lone Wanderer back to help her into stopping an outright civil war in their community, then, quoting almost verbatim the Overseer from Fallout, blames the civil war on him, banishing the Lone Wanderer forever. Owing to the sandbox quality of the modern Fallout games, you can still shoot her in the face
At least, if Amata's dad, the Overseer is killed. If he instead is talked down, not only is the nigh-verbatim quote from the Vault Dweller's Overseer left unsaid, but Amata's phrasing indicates that she herself doesn't blame the Lone Wanderer for the civil war — she just believes that others do, and that the Wanderer's presence will keep wounds open and increase tensions at a time when stability is critical for the Vault.
Link in The Legend of Zelda: Ocarina of Time. After being in limbo for 7 years he's grown up only to find that all his friends haven't. Turns out he's a different species to them anyway. They don't recognize him and many of them actually miss the child Link that left. Link seems to decide not to tell them (though Mido might know).
Jak and Daxter in Jak 2 They are in their old homeland only hundreds of years in the future.
Which actually turns out to be Jak's real time as the whole game revolves around making sure his younger self gets sent back in time to help fulfill The Prophecy.
The original Dragon Age: Origins had a mild example, or at least one that's not drawn as much attention to: if you befriended Sten and speak to him after defeating the Archdemon, he'll suggest that Seheron might not be quite the same to him as it would have been, since your adventures have changed his view of the world somewhat. This is especially true if your Warden is a female mage, since Qunari believe women are not competent warriors and mages aren't even people, and you've just killed both of those ideas. His writer Mary Kirby says he may even have had to spend some time with the Ben-Hassrath for all the strange ideas he's picked up (though Those Who Speak shows he's reintegrated pretty well, if being promoted to Arishok is any indication). If you didn't befriend him, he'll just be happy to be able to go home and get away from Ferelden's strangeness.
Dragon Age II: All that's left of what Hawke's mother had in Kirkwall is a bitter brother to remind her of what she'd lost. When Aveline asks Hawke about returning to Lothering, he/she can reply that it's no longer home.
Chrono Cross has an odd example. The hero gets sucked into an alternate dimension where he died as a child and everything's different...except that the next 20 hours of the game are in Another World and it takes that long to gain the ability to return to Home World. The player never really gets the opportunity to explore Home until then. Serge is a Heroic Mime, so we don't know his thoughts on this, but meta-wise this trope is in force for the player.
Prince Keifer in Dragon Quest VII. He had a fantastic adventure Trapped in Another World in a spinoff game years earlier, and ever since then has been struck with a lust for adventure and wandering which proves quite problematic for somebody trapped in palace life in a world with only a single, perfectly peaceful and rather small island. To say that he Jumped at the Call is an understatement; the only reason anybody found the call is because he spent the years between the spinoff and the game proper going over the island with a fine-toothed comb for something interesting.
Baldur's Gate 2 has an example of this in the epilogue for one of the characters: Imoen briefly returns to Candlekeep, but finds it smaller than she remembers, and goes on to adventure with various other famous heroes in the setting.
At the end of Inverloch, Kayn'dar recovers his identity and reveals that he's capable of healing Severed elves. Lei'ella, who was exiled when she was a preteen, finds that she's long since accepted mortality and doesn't want to tacitly support the people who exiled her by erasing what made her different, so she stays as she is and joins human society with Varden.
This happened to Adam Dodd when he finally arrived back home after winning season one of Survival of the Fittest. He eventually moved across the country as part of his attempt to cope with his experiences on the island.
In the Arthur episode "Buster's Back", Buster Baxter returns to Elwood after traveling with his father, a pilot. When he came back, a lot of things had changed, including his friends loving a clown show they all hated before he left.
Teen Titans has this as the theme of the series finale ("Things Change").
Zuko lives this trope for the first half of Season 3 of Avatar: The Last Airbender. While it wasn't exactly his home, Aang was rather alienated by the changes made to the Northern Air Temple so refugees could move in, but came to accept that it's their home now.
In one episode of Justice League, it is revealed that Green Lantern's greatest fear is that this has happened to him, and that he's become nothing more than an extension of his ring.
Parodied in South Park where a man was frozen in ice for three years and can't adjust to life in 1999.
This is the origin of the common expression, "You can't go home again." Your "home" will change in your absence and will never be quite the same as you remember.
Also, "You can never step into the same river twice", even if it looks the same, it's not the same water you stepped in the first time because the river kept on flowing in the interval.
Returning military veterans (not just combat vets) often feel this way when they separate from active duty. It's not a coincidence so many of the Literature examples above were by veterans. One WWI song fits the emotion: " “How Ya Gonna To Keep 'Em Down On The Farm? (After They've Seen Paree?)”
People who emigrate to another country will get this feeling after returning to their original country after many years. The language and customs have changed enough that you have a hard time communicating even if you are still a fluent speaker.
Potentially taken Up to Eleven if: a) their home country is not known to be embracing diversity/individualism; and/or b) the person lived abroad during his/her childhood years.
Step 1: Go to college. Step 2: Graduate, drop out, or transfer. Step 3: Wait two/three years. Step 4: Come back and watch as you recognize barely anyone.
Some colleges actually put together pamphlets and other resources to help exchange students cope with "reverse culture shock" or "reverse homesickness." When a student spends a semester abroad, it's often enough for them to put down a certain amount of roots, so when they come back home, they miss it.
Taken Up to Eleven when the Jews came to settle in what eventually became Israel. Now just imagine what might happen if the Roma people ever decide to go back to Punjab...
Another college example: coming from a lower-class background. Over time, trips back home will become more and more alienating as you no longer quite fit with the people around you.
Modern communication technology has changed this somewhat, but visiting home in a rural area after being in a more urban environment for a period of time, for whatever reason, often caused this: you often don't even have minor things like popular entertainment in common anymore. Before satellite TV and radio and widespread internet connectivity, people at "home" wouldn't have had as many options to be exposed to different genres of music, TV shows, and movies.