Capt. Charles T. Baker (voice of DWAYNE JOHNSON) is an American astronaut who's just traveled across the cosmos to claim Planet 51 for Earth. To his shock and initial horror, he's landed in Glipforg, a place inhabited by civilized, green-skinned and four-fingered beings who exist in a slightly futuristic yet retro version of 1950s America and coincidentally or not, speak English.
One of them is Lem (voice of JUSTIN LONG), a teenager who's just been named assistant curator at the local planetarium, a promotion he hopes might impress his next door neighbor, Neera (voice of JESSICA BIEL). He has a crush on her -- something not missed by her younger brother, Eckle (voice of FREDDIE BENEDICT) -- but doesn't know how to proceed. That's unlike his more carefree friend, Skiff (voice of SEAN WILLIAM SCOTT), who works at the local comic book store, or hippie Glar (voice of ALAN MARRIOTT) whose social protesting has grabbed Neera's interest.
But Lem has bigger fish to fry when he ends up being Capt. Baker's unintentional and initially unwilling accomplice to harbor the astronaut and get him back to his spaceship. That goal quickly becomes complicated upon the arrival of the army, led by General Grawl (voice of GARY OLDMAN) who wants the alien captured. He gets his advice from Professor Kipple (voice of JOHN CLEESE) who spreads rumors about such invaders, such as them turning the locals into zombies, his paranoia no doubt fueled by such related films.
From that point on, Lem does what he can to help Capt. Baker as they and their friends try to avoid Grawl, his men, and Kipple who wants the astronaut's brain for testing.