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The story begins with two teenagers being attacked by a "humaniac," a horrendous one-eyed monster that comes down to the planet to turn everyone into zombies and take over the world. Then it is revealed that this is merely a movie, though the plot resembles classic 1950s science fiction films.

Outside the theater is Planet 51, a world populated by little green aliens who live in a society similar to 1950s USA. Lem (Justin Long) is a teenaged alien who has just gotten a job at the local planetarium museum, and his family and friends are excited about it. His best friend Skiff (Seann William Scott), a geeky alien teen who works at the local comic book store, is a huge fan of the "Humaniacs" films.

When Lem gets home, he asks his next door neighbor and friend, Eckle (Freddie Benedict) about Neera (Jessica Biel), who is Lem's long-time crush. Lem's family is holding a barbecue with the neighbors. Neera is at the barbecue, but when Lem attempts to ask her out, he keeps being interrupted by Neera's hippie friend, Glar.

Meanwhile, a mysterious spacecraft pulls into orbit around Planet 51, sending out a blinking red signal. Down on the planet, under a hidden army base called "Base 9", the aliens' version of Area 51, there is a basement filled with artifacts from Earth. One artifact "wakes up" from the signal; it is a wheeled probe with artificial intelligence, named "Rover." Rover breaks out of the basement and escapes to perform its primary mission: to find the astronaut. Its secondary mission is to collect rocks, similar to Wall-E gathering garbage for compacting. The army becomes suspicious of Rover's escape and begins to look into its activity.
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