At Wellman College, thousands of hamsters overrun the campus, due to the massively obese, yet loving and kind-hearted, professor Sherman Klump (Eddie Murphy), who accidentally releases them due to his wide belly always accidentally hitting the button when he turns around. Meanwhile, Sherman has constructed an experimental formula that reconstructs human DNA in a way that allows them to lose weight instantaneously.
After finding success with a DNA restructuring formula in the first film, Sherman Klump has created another formula which enables those who take it to find the Fountain of Youth. He has also met and fallen in love with a colleague, Denise Gaines, who has developed a method to isolate genetic material and later becomes his fiancée. Together, their work has enabled Wellman College to receive a $150 million award from a pharmaceutical firm to the excitement of Dean Richmond. Despite his good fortune, Sherman has a major problem: the personality of his vanquished alter ego, Buddy Love, is still ingrained inside him and causes him to act out in the same crass manner Buddy does.
At a satellite base in Northern Germany, a worker named Freidrich, who is delivering secret codes finds a Cocker Spaniel puppy outside his office. He takes the puppy inside and shows it to his Bloodhound Rex. Rex senses that something is wrong with the dog and barks at it, making the worker take him outside. Both get locked out of the office. Rex looks through the window and sees the puppy taking pictures of the secret codes and revealing itself to be an evil female hairless Sphynx cat named Kitty Galore in disguise. Rex turns out to be a dog agent and reports to HQ.
Austrian Research geneticist Dr. Alex Hesse (Arnold Schwarzenegger) has a nightmare about infants urinating in a library. In the real world, he and his colleague Dr. Larry Arbogast (Danny DeVito), an obstetrician and gynecologist, have invented a fertility drug, "Expectane", that is supposed to reduce the chances of a woman's body rejecting an embryo and thus prevent a miscarriage. Unfortunately, they are not allowed to test it on women since the Food and Drug Administration has not yet approved the drug; so Hesse and Arbogast move forward in their research. In response, Hesse breaks into the laboratory and locks himself in. The head of the review board, Noah Banes (Frank Langella), informs Arbogast that while the FDA has denied their team the right of human experimentation, the team has managed to receive a donation from fellow geneticist Dr. Diana Reddin (Emma Thompson) from the ovum cryogenics department. When Hesse questions the chances of a woman taking an unapproved drug during pregnancy, Arbogast reveals that there is no need to identify the gender of the experiment and convinces Hesse to impregnate himself, using an ovum codenamed "Junior".
On Planet 51, green humanoids with snail-like feelers and pointed ears live peacefully in a society reminiscent of 1950s America, but with alien technology and with 1950s-themed alien homes. In the town of Glipforg, Lem is a teenage boy 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. At a barbecue Neera's family is having, Lem tries to ask her on a date, but her hippie friend, Glar, keeps interrupting with his protest songs.
The film begins with a Broadway-style number "So Long, and Thanks for All the Fish", sung by the dolphins of the world, who are aware of the Earth's impending doom. At the end, they all jump out of the oceans and into space, leaving Earth for good.
In response to a record high crime rate in Johannesburg, the South African government purchases a squadron of state-of-the-art, armour-plated attack robots from weapons manufacturer Tetravaal, developed by Deon Wilson. A competing project is the remotely controlled MOOSE, developed by soldier-turned-engineer Vincent Moore. Deon is praised for Tetravaal's success but Vincent grows jealous when the police are unwilling to give his heavy weapons platform equal attention. At home, Deon creates a prototype artificial intelligence that mimics a human mind to the point of feeling emotions and having opinions, but Tetravaal CEO Michelle Bradley refuses to let him test the A.I. on a police robot. Undeterred, Deon steals a recently damaged robot before it is destroyed and puts it in his van, along with the "guard key" needed to update the robot's software. On his way home, he is kidnapped by a group of gangsters, Ninja, Yolandi, and Amerika, who threaten to kill him unless he reprograms a police robot to fight for them. Deon installs the new software into the damaged robot, which responds with childlike terror upon powering up. Deon and Yolandi calm the robot, teaching it words and naming it "Chappie". Despite Deon wanting to stay with the robot, Ninja forces him out of their hideout.
Two months have passed since a mutated strain of mad cow disease mutated into "mad person disease" that became "mad zombie disease" which overran the entire United States population, turning American people into vicious zombies. Unaffected college student "Columbus" (Jesse Eisenberg) is making his way from his college dorm in Austin, Texas to Columbus, Ohio to see whether his parents are still alive. He encounters "Tallahassee" (Woody Harrelson), another survivor who is particularly violent in killing zombies. Though he does not appear to be sociable, Tallahassee reluctantly allows Columbus to travel with him. Tallahassee mentions he misses his "puppy" that was killed by zombies, as well as his affinity for Twinkies, which he actively tries to find. Survivors of the zombie epidemic have learned that it is best not to grow attached to other survivors, because they could die at any moment, so many have taken to using their city of origin as nicknames, i.e. "Columbus" is from Columbus, Ohio.
Joanna Eberhart (Nicole Kidman) is a successful reality television executive producer. She is fired after her latest project, a show called I Can Do Better, where spouses choose between each other or prostitutes, results in one of the jilted men going on a shooting spree and attempts to assassinate Joanna, and she has a nervous breakdown. With her husband Walter (Matthew Broderick) and their two children, they move from Manhattan to Stepford, a quiet Connecticut suburb.
In Kentucky, a family watches an enormous horde of cattle running past their home, having caught fire, and a flying saucer leaving Earth. The ship explodes before it returns to Mars, and hundreds of other Martian ships leave Mars and head towards Earth.
Wayne Grey (Seann William Scott), a fireman trainee practicing in a shack in the desert near Glen Canyon, Arizona, sees a meteor strike his car and land in an underground cavern. College professor Ira Kane (David Duchovny) and his colleague, geology professor Harry Block (Orlando Jones), investigate, taking a sample of strange blue liquid that oozes from it. Ira discovers that it harbors extraterrestrial single-celled nitrogen-based organisms multiplying exponentially, condensing millions of years of evolution within a matter of hours. The next day, they take the science class to survey the meteor site and find it already surrounded by evolved oxygen-converting fungi and alien flatworms. Ira and Harry discover that the cells and organisms reproduce rapidly through mitosis after seeing one of the flatworms they collected in a jar split into another.
Graeme Willy (Simon Pegg) and Clive Gollings (Nick Frost) are British comic book enthusiasts and best friends who travel to the United States to attend the annual San Diego Comic-Con International, and to take a road trip through the American Southwest to visit sites significant to UFO lore. While driving on a remote desert highway at night, Graeme and Clive observe a car driving erratically and then crash. They stop to investigate and offer assistance to the driver, who turns out to be an alien named Paul (voiced by Seth Rogen). Clive faints, but Graeme agrees to assist Paul and gives him a ride.
Three thousand years ago, an Aztec warlord named Yaotl and his four generals discover a portal opening into a parallel universe which is said to have great power. Yaotl becomes immortal but at a high price, as his four generals were turned to stone. The portal releases thirteen immortal monsters that destroy his army as well as his enemies. In the present, the Teenage Mutant Ninja Turtles have grown apart. After defeating the Shredder, Master Splinter has sent Leonardo to Central America for training. Donatello works as an IT specialist, Michelangelo works as a birthday party entertainer called Cowabunga Carl and Raphael works at night as a vigilante nicknamed Nightwatcher. April O'Neil operates a company that locates and acquires relics for collectors with the help of her boyfriend, Casey Jones.
The film follows the cast of a once-popular television space-drama series called Galaxy Quest. The fictional series starred Jason Nesmith (Allen) as the commander of a spaceship called the NSEA Protector, Alexander Dane (Rickman) as the ship's alien science officer, Fred Kwan (Shalhoub) as the chief engineer, Gwen DeMarco (Weaver) as the computer officer and Tommy Webber (Mitchell) as a precocious child pilot. Guy Fleegman (Rockwell) played an unnamed security officer, who was quickly killed off in his only appearance on the show.
Dr. Frederick Frankenstein (Gene Wilder) is a physician lecturer at an American medical school and engaged to the tightly wound socialite Elizabeth (Madeline Kahn). He becomes exasperated when anyone brings up the subject of his grandfather, the infamous mad scientist. To disassociate himself from his forebear, Frederick insists that his surname is pronounced "Fronkensteen."