Chuck is a 50-year-old human astronaut who gets stranded on Planet 51.
- The Big Guy: He is the biggest main character in the movie.
- Decoy Protagonist: He is first billed in the opening credits and top-billed on the DVD cover, but the real protagonist is Lem.
- Humans Are Ugly: Chuck is quite handsome and has had his likeness posted on many Earth magazines. However, by Planet 51 standards, he's hideously ugly and is assumed to be a threat because of this.
- Token Human: He's the only human character in the entire film. There is no sight of Earth nor any other humans besides him.
Lem is a 13-year-old who works in the planetarium. When he first meets Chuck, he agrees to help him stop his spaceship. When Chuck is captured by Kipple, he leads a group of friends on a rescue mission to save him and help them stop the ship.
- All of the Other Reindeer: This is justified since he was a Attention Whore.
- Big, Thin, Short Trio: The thin to Skiff's big and Eckle's short.
- Butt-Monkey: He is clumsy, but cheerful.
- Cloudcuckoolander: He is ditzy and sometimes forgetful.
Lem's 15-year-old neighbor and crush, which she actually reciprocates.
- Beauty Brainsand Brawn: The beauty to Skiff's brawn and Eckle's brains.
- Green-Skinned Space Babe
- Nice Girl: She's one of the few residents of Planet 51 who doesn't believe Chuck to be evil and doesn't require much motivation to help rescue him during the climax.
General Grawl is a 69-year-old general who relentlessly pursues Chuck.
- Anti-Villain: While he's relentless in his pursuit of Chuck, it's because he's under the mistaken belief that he poses a danger to his planet. Once he relizes that Chuck isn't dangerous, he orders his men to stand down and parts with Chuck on friendly terms.
- Big Bad: He is falsely the main antagonist of the film and Kipple working for him is all part of his Evil Plan.
- Big Bad Duumvirate: With Kipple.
- The Dragon: To Kipple.
- Laughably Evil: Of the Comically Serious variety.
Skiff is the 14-year-old best friend to Lem and a friend of Eckle's.
- Big Damn Heroes: He and Eckle save Lem from being abducted by Chuck, whom they mistake as the alien.
- Big, Thin, Short Trio: The big to Lem's thin and Eckle's short.
- Butt-Monkey: When he is disturbed by Rover.
- Cloud Cuckoo Lander: He's the cookiest of Lem's friends and is constantly making conspiracy theories about alien invasion.
- Deadpan Snarker: Has a few moments around Rover.
- The Lancer: To Lem.
- Those Two Guys: With Eckle.
Eckle is Neera's 8-year-old brother who speaks in a British accent.
- Big, Thin, Short Trio: The short to Lem's thin and Skiff's big.
- Big Damn Heroes: He and Skiff save Lem from being abducted by Chuck, whom they mistake as the alien.
- Keet: Always bursting around with energy.
- The Napoleon: He joins the final battle with his Big Guy antics.
- Never Bareheaded: He always wears a red baseball cap, backwards.
- Those Two Guys: With Skiff.
Professor Kipple is an 80-year-old scientist who helps General Grawl to get rid of Chuck's brain. He is Grawl's henchman. At The Stinger, he is revealed to be the Big Bad of the movie.
- Badass Bookworm: He is smart, but evil.
- Big Bad: He is the main antagonist of the movie.
- Big Bad Duumvirate: With Grawl.
- The Dragon: To Grawl... or so it seems. It's revealed that he accepts Grawl's help as part of his evil plan.
- Evil Chancellor: He is the main henchman to General Grawl.
- Evil Laugh: He has one at the climax of the movie when he prepated to take Chuck's brain out of his head.
- The Napoleon: He is four feet tall and has quite a bad temper.
- What Happened to the Mouse?: He was last seen during the final battle getting presumedly killed by Lem. He reappears in the post-credits scene, having survived and is revealed to be the true Big Bad of the movie.