In Madagascar 3: Europe's Most Wanted, Alex and his friends finally make it back to the Central Park Zoo in New York City, only to realize that they have grown to prefer being free after all.
A major conflict in Inside Out, where Riley and her Emotions come to terms with leaving behind Minnesota.
Moses in The Prince of Egypt, where he flees from Egypt after accidentally killing a slave-master, despite Ramses pleas with him to stay. This also happens again, later, after him and the Isrealites successfully cross the parted Red Sea, he looks back sadly and says, "Goodbye, brother."
A major element in 2007's Transformers movie. The civil war on Cybertron damaged the planet's surface, and the Allspark being destroyed means that the planet will die eventually. At the end of Transformers: Dark of the Moon, the Space Bridge's destruction possibly causes Cybertron to collapse on itself, forever preventing the Autobots from returning to their old home.
In Grosse Pointe Blank, John Cusack's character, Martin Blank, return to his home town for a reunion. While there, he visits his childhood home, only to find that it's become a convenience store. This causes him to say the line, "You can never go home again, but I guess you can shop there."
In Inception, the sole reason for Cobb to accept the mission is that Saito has enough influence to allow him to return home to his children. He is wanted by the police as the primary suspect for his wife's death and went into hiding, leaving his children behind with their grandparents. In a particularly painful twist to the old plot, his wife believed that the real world was a shared dream of them and that they would have to die to wake up in the real world. So she set up her own suicide making it appear as if he murdered her, directly mentioning that he would no longer be able to return to his family in the supposed dream, in the hope that he would also kill himself so they could both wake up in the real world.
In Star Trek (2009), Spock and Spock Prime both wind up afflicted by this trope: Spock because Vulcan has just imploded and Spock Prime because he's marooned in another timeline...and Vulcan has just imploded.
And, of course, the Big Bad, Nero, is in the same boat, thanks to the supernova that took out Romulus and his subsequent time-traveling.
The Searchers ends with John Wayne leaving because his behavior has alienated his family.
In the Forrest Gump movie, Forrest has Jenny's childhood house razed in order to bring closure to years of abuse by her father.
Paint Your Wagon features this lyric: "Home is made for coming from, for dreams of going to/ which, with any luck will never come true."
In the film version of The Hitchhiker's Guide to the Galaxy, the Earth is restored, but Arthur Dent decides that the world would be a better place without him, having fallen in love with Trillian and wanting to share her wanderlust.
The Hunt for Red October. Marco Ramius makes sure that his defection will be real by burning all of the bridges behind him.
In Idiocracy, where the main characters, after hibernating in pods for 500 years, wake up to a world of naturally selected idiots.
In Harlem Nights (1989), Quick (Eddie Murphy) and Sugar Ray (Richard Pryor) pull The Caper that results in the death of the major rival crime boss.. Knowing the danger of what they have done, they take a last wistful look at the New York skyline before bidding the city goodbye.
The movie Silent Hill after Rose and Sharon leave Silent Hill and appear to arrive back home, they are still in another reality because they entered the world of Silent Hill. Thus they can never truly return home.
It takes Columbus a while to come to this conclusion in Zombieland. He wants to get back to Ohio to see if his family is still alive (although he eventually admits that that wouldn't mean much even if they were). He reacts appropriately when Wichita tells him that that's a pretty fruitless venture, as it's "a total ghost town". He still doesn't quite get it until he's about to leave and he realizes that he really can't go back home.
Done in the movie Vamp, when Keith finds his friend AJ.
AJ: You don't get it do you? For me, home is a million miles away now. Home is on another planet. (He hunches over before rising with fangs and gold eyes) I'm a fucking zombie now!
In About Schmidt, during one of his excursions on the way to his daughter's wedding, Schmidt goes to visit his childhood home from many years ago, only to find a tyre shop now standing in its place. He still goes inside and tries to reminisce, to the bemusement of the clerk.
In Howard the Duck this is what happens to the title character in order to save the Earth.
Ash's fate in the original ending of Army of Darkness, in which he drinks too many drops of a sleeping potion and wakes up after the apocalypse.
Wonder Woman (2017): Hippolyta tearfully warns Diana that should she choose to leave Themyscira, she can never return. Diana acknowledges this, but still chooses to fulfill her purpose.
X2: X-Men United: After Stryker's raid on the school, Bobby, Rogue, Logan and Pyro stop by the Drake family house in hopes of regrouping, which in the process reveals Bobby's mutant abilities to his parents. His own brother calls the police and reports them as a threat despite the mutants not harbouring any ill intentions. After Pyro stupidly attacks the officers in the standoff that follows, Bobby is forced to flee with the others knowing he can never come back.
X-Men Origins: Wolverine: Invoked by a young Victor Creed after James Howlett kills his family's groundskeeper. The boys are being pursued by lawmen and search dogs.
Caesar visits his old home for the first time in years. However, it has gone into ruins and his former master is long gone.
Exploited by Koba as he set the apes' territory on the fire and shoots Caesar, blaming both acts on the humans. And without their home, the apes are forced to go into war.
In Teenage Mutant Ninja Turtles (1990), the Foot find out where the Turtles' lair is and kidnap Splinter, forcing the Turtles to stay at April's...until the Foot find them there and attack. This is the reason why the Turtles are at April's new apartment in the beginning of the sequel Secret of the Ooze and looking for a new home; "We could always go back to the old sewer den." "Oh, right, Raph. It's a little tough, when about five hundred members of the Foot clan know where you live."
Star Wars: Word of God states that the reason Obi-Wan had Luke Skywalker go to Tatooine after birth to live with the Lars family despite it being Vader's home planet is that Darth Vader is unwilling to ever return to Tatooine due to painful memories of the place.
By the end of A New Hope, Luke has lost pretty much everything. His aunt and uncle are dead, he can't go back to the farm, because he would have been killed even before the Death Star incident thanks to the droids. His mentor dies, and Biggs, his best friend, dies being a human shield protecting him during the Battle of Yavin. This all takes place over the course of a few days tops. A few expanded universe novels imply that the only thing that got Luke though was the adrenaline and the fact that he was given practically no downtime for him to think about it. Subverted in Return of the Jedi, when he has to return to rescue Han Solo from Jabba the Hutt.
In Suffragette, when Maud returns from a suffrage meeting, her husband doesn't let her enter their shared home and leaves her to sleep on the streets. Fortunately the suffrage movement is prepared for such cases, and a room with affordable rent is provided almost immediately.
At the end of Captain America: The First Avenger, Steve Rogers wakes up in the present day, approximately 65 years after he crashed the Valkyrie into the Arctic to prevent the bombing of New York City. Most of the familiar landmarks of New York have changed, and almost everyone he knew is dead. He can go back to Brooklyn, but he can never truly go home.
In the ending of Thor: Ragnarok, Surtur destroys Asgard in a massive explosion killing himself Hela and her Berserkers army while the Asgardians (with Thor as their new king) escape on a spaceship to find a new home.
In Encino Man, when the school takes a trip to the museum, Link stares at the exhibits of cavemen and comes to the horrified realization of what happened to him, and that the prehistoric world he knows is gone forever.