A theme in A Series of Unfortunate Events. At one point, Snicket even parodies this trope directly. "People say that you can't go home again, though they may not have been talking to you."
This happens in Animorphs. Ax tries to get home early on, but then decides it's better to help out on Earth and wait until the Andalites arrive.
Thomas Wolfe's novel You Can't Go Home Again is the Trope Namer, and combines elements of both this and Stranger in a Familiar Land. George Webber, an author, literally can't go back to his small-town home because the residents think his debut book gave them a bad name and threaten to kill him over it, and the recent development boom has made the town almost unrecognizable compared to how George remembered it as a kid. Plus there's the deal with the Nazis taking all the magic out of 1930's Germany, and the whole Great Depression thing.
The titular Ghosts of Dan Abnett's Warhammer 40,000: Gaunt's Ghosts earned their nickname in part because their homeworld of Tanith was destroyed by Chaos on the day of their Founding. Later, after the novel Necropolis, thousands of survivors from Vervunhive join the Tanith after their home hive-city is so badly damaged in a battle against Chaos that the whole hive is rendered uninhabitable.
In The Silmarillion, Maglor. He was the only survivor of the Noldor who was not allowed to return to the Undying Lands because of his crimes.
Arthur Dent and Trillian in Douglas Adams's The Hitchhiker's Guide to the Galaxy. The Earth is gone for good, as are Arthur, Trillian and Ford. Even though there's a sixth book on the horizon, which means Arthur and Ford, at least, is still around in some form, I doubt the Earth's coming back.
Even if Earth II was introduced, Adams' screenplay of the film version seems to indicate Arthur might not wish to return anyway.
Neverwhere by Neil Gaiman. Richard Mayhew no longer exists to his "London Above" life and most of his adventure helping Door avenge her family's deaths is because he thinks that when he does that, he'll find a way to go home. He doesn't fit in anymore when he ends up home in the denouement, so he returns to London Below.
In the film version, it's made clear that he only returns to keep his word to his original Love Interest and give her some closure. He also discovers that Yvaine would turn to dust on our side of the Wall.
The Homeward Bounders by Diana Wynne Jones makes a feature of this trope, with the titular characters traveling from world to world (unwillingly, unagingly) hoping that eventually they'll end up back home and stop. The main character discovers that "you can never go back" when he finally manages to get to his world. Decades have passed; his 'home' no longer exists anywhere in the multiverse.
It's implied that his home was our world circa 1905, and he returns sometime after WWII and the rise of wargames.
Throughout the latter half of Robert Jordan's The Wheel of Time series, Rand al'Thor has the ability to open a Cool Gate pretty much anywhere in the known world, and yet the closest he comes to going home is when he gives someone a lift there. He refuses to stick around, knowing that his presence would put his loved ones in danger.
In A Song of Ice and Fire, leaving your home of Winterfell is really not a good idea. You may end up dead, on the run from people who want you dead, held captive, or in sworn service of the Night's Watch. If you ever do make it back, Doomed Hometown.
Of all the characters who consider Winterfell their home and leave over the course of the first two books, only two return (three if you count Theon). Jeyne Poole's return can hardly be considered a good thing either, as she's being married off to the sadistic Ramsay Snow. Only Ser Rodrick Cassel returns under anything close to decent circumstances, and even he is later killed.
In The Scar, stand-alone sequel to Perdido Street Station, Bellis's primary objective is to get back to New Crobuzun, until her plans change when she realizes that she can't escape Armada.
In Android at Arms, the protagonist and his Salariki friend accidentally end up in an Alternate Universe via a Cool Gate that the protagonist knew of by reputation; they had taken a chance of hiding out in its vicinity to avoid pursuit, since it rarely went into operation, and had bad luck. The protagonist knows, thanks to his studies with his late father, that nobody taken by the Cool Gate has ever returned.
In The Beast Master, Earth has been destroyed in an interstellar war as of the beginning of the story; the titular character, a specialized kind of commando, chooses another planet to be sent to after the war. The military is (justifiably) worried about his state of mind, particularly since they haven't seen any of the obvious / expected reactions from him.
In The Crystal Gryphon, Ithkrypt (the capital of Ithdale) and Ulmsdale are both destroyed by Functional Magic to keep them out of the hands of invaders (though in separate incidents). The latter had no survivors other than the Fish out of Water male protagonist, as far as he could tell; he joined up with the refugees from Ithdale (who include the female protagonist, their leader) to try to get them out of harm's way.
In the Time Traders book Echoes in Time (co-written with Sherwood Smith), this is the fate of some human time travelers who go back into the far past on another planet. The rescue mission sent to retrieve them learns that the team survived, but were physically changed so that they could not survive returning to Earth, so they had made the best of a bad situation.
In Here Abide Monsters, the protagonists are swept into Another Dimension through a Cool Gate, and learn that they are Trapped in Another World, called Avalon. Such refugees from our world fall into two groups: those who accept an offer by The Fair Folk to be assimilated, and those who persist as rootless wanderers and are treated as prey by various creatures.
In Wraiths Out of Time, the protagonist changes places with her Alternate Universe counterpart, who dies in the process. Since she has no strong anchor to take her home, she cannot go back. In addition, the titular characters - the victims of a Mad Scientist - are in their wraith-state due to a similar problem.
In Robert Sheckley's Dimension of Miracles the protagonist spends most of the book trying to get home.
In Star Wars, Alderaan is blown up. This is mined for much drama and angst in the Expanded Universe, with the various Alderaanians who were offworld at the time.
Not to mention Luke's home, which is destroyed by Imperial Stormtroopers.
It's actually used a lot like Bonding Over Dead Parents in Galaxy of Fear; the Alderaanian kids, Luke, and Leia commiserate a bit. Later, talking about Alderaan is what gets the vengeful wraiths of the Kivans to let the kids go - they are in parallel straits.
Spader and Gunny from the Pendragon series ends up like this after Bobby tries to pull his Acolytes through the flume from Eelong to Zadaa, causing the Eelong flume to collapse and trap Spader and Gunny on a territory surrounded by catpeople for months (and like four books).
Those selected for training as Eternals in The End of Eternity could never return home, because home would no longer exist due to Reality Changes.
And, at the end, the main characters can't return to either the Eternity or their respective centuries because they have just erased the Eternity and changed the whole future history of humankind.
The short "Painwise" by James Tiptree Jr. featured a man whose nervous system had been played with. Anything that would cause him normally to feel pain would just cause him to see coloured lights. Turns out that his pain centers only kick in if he returns to Earth.
Eragon's house is blown up and later his home village's population evacuates and joins the Varden. Angela the fortune-teller even predicts that he will eventually leave Alagaesia altogether, never to return.
In The Forever War, decades and even centuries pass on Earth while the hero spends a few years on the front, due to relativistic trips to and from the black holes that make FTL travel possible.
Time Dilation plays into a short story by Nancy Etchemendy, where a woman follows the man she loves into space, then gives up her child to her mother on Earth after her husband dies. Decades have passed on Earth, and on top of all the strange fashion, technology, and slang freaking her out, she fears her mother might be dead and her presumably middle-aged son hates her. To her surprise her mother is alive and her son is only five years younger then she is since he went into space too — and they're both happy to see her.
In David Eddings's Belgariad Garion spends much of the first series wistfully wishing he could return to Faldor's farm where he grew up. This becomes much more evident when he discovers that he is the heir to the Rivan throne, with all the responsibility and weight that carries. Oh, and he's supposed to challenge the insane god Torak in mortal combat. You know, run of the mill stuff. When he finally manages to visit, he knows his life is now somewhere else and makes his peace.
The setup of Jean Shepherd's In God We Trust, All Others Pay Cash is a expatriate midwesterner, now a NYC resident, going back to his home town to write an article. The book is a collection of short stories relating scenes of his youth there. It becomes clear that he doesn't belong there anymore.
A major theme in Vilhelm Moberg's Emigrant Suite. Kristina is very homesick in America and it doesn't help that she knows she can never go back home again and never see her family and friends again.
Poul Anderson's The Long Way Home involved astronauts on a year-long voyage with a new FTL drive coming home to Earth to discover the drive wasn't faster than light after all* Those aboard perceived the travel as being instantaneous, but it was really at exactly the speed of light ... meaning the past year of exploring had actually taken roughly five thousand years....
Kvothe from The Name of the Wind is of the Edema Ruh, who are travelling performers similar to much more honourable gypsies; their homes are their caravans. When his troupe was killed and their caravans destroyed, he found he had no home to go to.
Ayla from Earth's Children experiences this twice - first when her home is destroyed in an earthquake as a child, then when she's exiled from the Clan. Every other home she left voluntarily to go with Jondolar to the Zelandonii.
Sisterhood Series by Fern Michaels: The series definitely has fun with this! The book Sweet Revenge has Isabelle Flanders stating the trope after she talks her old fiance Bobby Harcourt, and it's made clear that it's too late for them to restart the relationship they once had. At the end of the book Free Fall, the Vigilantes become fugitives and a major plot point involves them waiting to be pardoned by the President. They do get pardoned by the book Game Over, but they still go through a few more hurdles. By the last book Home Free, the Vigilantes finally get some homes, and their lives are certainly different from what they had before.
In one of the Warrior Cats graphic novel trilogies, after Graystripe is captured by Twolegs, it takes him several moons to escape and find his way back to the forest... but that's when he realizes there is no forest - it's been destroyed by Twolegs. He eventually manages to find his way to the Clans' new home.
In Jack Campbell's Lost Fleet novel Invincible, Geary. He can't go home because he slept through a century and everyone he ever knew is dead. (His planet's still there, but the Living Legend that grew up about him means he doesn't want to.)
In Chanters of Tremaris, Calwyn runs away from her home village of Antaris and only returns when she has lost her magical powers, to find that her beloved High Priestess has been replaced by her Jerkass second-in-command, Marna, who has instituted a reign of terror and is killing priestesses in an attempt at disease control, and will kill Calwyn and her friends if they are found. Not 'cause they're sick, though. Just 'cause Marna really, really hates them.
A Brother's Price has Jerin Whistler leaving the farm he was raised on to go get married - in this world, husbands move into their wives' households - and as he's going thinking unhappily that this is it - if the women who pick him are kind they will take him to visit, but even then he will never call it home again.
In Andre Norton's Catseye, Troy is a war refugee trapped in the grim settlement where they eke out a marginal existence.
In Harry Turtledove's Homeward Bound, Sam Yeager is told in so many words that he's no longer welcome on Earth and is better off joining the crew of the Admiral Peary on its way to the Race's homeworld. The journey to Tau Ceti takes 30 years, although the entire crew is in cryo-stasis. Sam's son and daughter-in-law join him, though. However, a few months after their arrival to Home, the Commodore Perry joins them using the first ever FTL drive, having taken only 5 weeks. The crew of the Perry is under strict orders not to bring Yeager back, but they are forced to do so, averting this trope.
In an earlier novel, Glen Johnson, a combat Space Plane pilot decides to investigate a space station being constructed in secret by the US government. He fakes an emergency and docks with the station, only to discover that it's humanity's first nuclear-powered spaceship. Once the Lewis and Clark breaks orbit on its journey to the Asteroid Belt, Johnson is informed by the ship's commandant that he, like every member of the crew, is on the ship for good. Ditto for the crew of the second ship, the Christopher Columbus.
Gertrude Stein famously wrote of her hometown of Oakland, "there is no there there," referring to this trope. After returning to America from a long stay in France, she discovered that her childhood home was unrecognizable.
At the end of Creator/Stephen Baxter's Ring, not only are the protagonists stuck 5 million years after their mission started, but they're stuck in another universe.
At the end of Enderís Game, Ender Wiggin realizes that he can't return to his family on Earth after the end of the Formic War, since the political instability on Earth—caused by years of pent-up hostility between Russia and the USA finally erupting when they no longer have an extraterrestrial threat to unite against—means that all of the major powers on Earth either want to kill him or force him into military service. He also can't bear to return to a hero's welcome on Earth, since he's coping with the knowledge that he unwittingly wiped out an entire alien species. Instead, he accepts a post as a governor in Earth's extraterrestrial colonization program, knowing that the relativistic nature of space travel will make it impossible for him to ever see his family again.
Averted in The Underland Chronicles, mostly. This happens a bit in the Gregor the Overlander, but then Gregor goes on this quest to find his missing dad and all that. Otherwise they want him to go home. And then come back for the next 4 books.
True for the three main women in The Kingdom of Little Wounds. Ava lost most of her family at a young age, and more than that had to be sent away after a miscarriage. Midi doesn't know where home even is for her. And Isabel, as is the nature of political marriage, will never see France again.