On Planet 51, green humanoids with snail-like feelers and pointed ears live peacefully in a society reminiscent of the 1950s United States, but with alien technology and 1950s-themed alien homes. In the town of Glipforg, Lem is a teenager with a new part-time job at the local planetarium and a long-time crush on his neighbor, Neera. His best friend is Skiff, a big fan of the Humaniacs films. Lem tries to ask Neera on a date, but her hippie friend, Glar, keeps interrupting with his protest songs.
A mysterious spacecraft goes into orbit around Planet 51 and sends out a signal. On Planet 51, under a secret Army installation called Base 9 (their version of Area 51), there is a basement filled with Earth artifacts including robotic satellites launched by the United States and the Soviet Union. The spacecraft’s signal activates Rover, a wheeled A.I. probe. Rover escapes, following a program to locate the newly arrived astronaut. The Planetary Army becomes suspicious after Rover’s escape and begins to investigate.
The spacecraft touches down in Lem’s backyard; NASA astronaut Charles “Chuck” T. Baker emerges. As Chuck plants the United States flag, he steps on a “rubber ducky” someone left on the ground. Everyone stares, and Chuck tries to get back into his module. Shocked when he realizes he is on an inhabited planet, Chuck runs about wildly and hides at the planetarium as the Army arrives on the scene. Planetary Army General Grawl consults Professor Kipple about the “alien invader”. The Army quarantines the area and asks citizens to start a local civil defense force to prevent the citizens from becoming “zombies”.
At the planetarium, Lem discovers Chuck’s hiding place. They are surprised to discover they speak the same language. Realizing this alien is no threat, Lem decides to help Chuck, hiding him in his bedroom for the night. Rover finds Chuck, who is very happy to see it. As the General and his men search Lem’s room, the group sneaks back into the planetarium with Chuck, who tells Lem he has “the right stuff”. Chuck also shows Lem the star that Earth orbits and how the universe is much bigger than Lem had thought. The next morning, the Army takes Chuck’s module to a secret location.
The next night is the premiere of a new Humaniacs movie, and Lem, Skiff and Chuck attend in costume as fans. Chuck introduces some new music as part of the contest and teaches Lem to dance. Things go well until Rover arrives: chaos ensues. General Grawl arrives and points out that Chuck’s U.S. flag insignia identifies him as the alien. Chuck is captured and unmasked. When Lem tries to keep him from being taken away, General Grawl labels Lem a zombie, and Professor Kipple announces he will dissect both their brains. To protect Lem, Chuck pretends to “release” him from his control. Lem is proclaimed a hero, and Chuck and Rover are taken away.
At Base 9, General Grawl interrogates Chuck, and an accidental gunshot starts a complicated chain reaction with soldiers shooting at each other. General Grawl thinks Chuck is resisting his demands and allows Professor Kipple to have a go at dissecting Chuck’s brain. Lem gets his job back at the planetarium and is permitted to speak about the incident on TV, but cannot fully accept the honor. He feels terrible about Chuck and decides to do the right thing. Neera, Skiff and Eckle join him to go off to rescue Chuck. The teens know luck is on their side when Rover shows up on the edge of town-he unscrewed the bolts holding together the armored vehicle in which he was imprisoned.
Rover sniffs out Chuck’s trail and leads them to an abandoned gas station in the desert. They look around, and Skiff sees a soda bottle in an old refrigerator. When he tries to take it, it opens up the entrance to Base 9. Lem has Glar distract the soldiers guarding the base with his protest group while the rest of them sneak into the base. They find Chuck strapped to a laboratory table, and Professor Kipple getting ready to remove his brain. Lem and his friends break in through the ceiling while Rover scares away the scientists, technicians, and guards. They release Chuck but set off alarms.
Rover helps the group find Chuck’s spacecraft, which was in a hangar. General Grawl warns that, if the “alien” tries to leave, he will blow up the hangar. To give Chuck his chance to escape, Lem initiates the 2-minute destruct countdown by pressing the self-destruct control button, which panics the guards into fleeing the underground base. In the resulting firestorm, the General is knocked unconscious. The teenagers and Rover get into the module, but Chuck rescues the General from the fire. Chuck pilots the ship into orbit around the planet, allowing the teens to experience outer space. Skiff and Eckle enjoy the weightlessness, General Grawl realizes Chuck has not turned him into a zombie, and Lem asks Neera out on a date. Chuck returns to the planet’s surface. Although the soldiers are ready to shoot anyone who appears, the General stops them. Finally, the inhabitants of Planet 51 see that Chuck came to their planet for peaceful purposes. Chuck lets Rover stay with Skiff and says his farewells to Planet 51. Chuck then leaves Planet 51 peacefully, accompanied by the alien pet dog seen throughout the film (who had sneaked aboard Chuck’s ship without anyone noticing, except its owner).
In an end scene Professor Kipple is seen emerging from Area 9 from a hatch, only to be seized and dragged away by two military test subjects of Kipple’s brain removal procedure who insist that the professor share the delightful experience of having his brain removed.