A meteor falls to Earth. At the same moment, a young man called Wayne Grey (Seann William Scott) is pretending that his mother has burned the house down because of falling sleep while smoking in bed. The mother is a dummy. He sees the meteor fall and runs away, runs because the meteor fell right over his car, leaving a huge crater.
Cut to GLEN CANYON COMMINUTY COLLEGE, in the morning
Dr Ira Kane (David Duchovny) is a professor who has just given almost all his students an A in their biology papers. Two overweight boys - siblings Deke and Danny Donald (Ethan Suplee and Michael Ray Bower) were the only ones who got a minus, because they confused the topic of their papers, talking about their uncle living in a "cell" instead of writing a paper about "cells" as in the cells which make up human bodies.
Professor of Geology Harry Phineas Block (Orlando Jones) checks a female student, Nadine (Katharine Towne) [who wants to be a nurse]'s examination and wonders whether she should try a different job, one where other people's lives are not dependent on her skills. She wants to be Miss Arizona, but her pageant consultant says that nursing studies would impress judges. Ira interrupts him to go to lunch.
They both go to check the meteor. Harry belongs to the USGS, the USA's geological service, so he can check the meteor. Harry presents Ira as his secretary to Sheriff Long (Michael Chapman). The guy from the beginning says that he was practicing for his fire-brigade entrance examination in the middle of the night. The hole made by the meteor looks like a cave, and the police officers are fooling around it and taking pictures of one another. Officer Sam Johnson (Pat Kilbane) asks Harry what he's doing there. Harry gives attitude, but Ira gets straight to the point, saying that they need to take some samples. Sam says that they (the police) already have all the photographic evidence they need. The meteor is still hot. When they hit it with an axe, it kind of bleeds. It's Ira who analyzes it under the microscope and he sees cells multiplying like crazy until they break the thin layers of glass in which they were put.
Harry is the volleyball coach as well. Ira runs to tell Harry about the ten base pairs DNA he's just found. Harry and Ira are already talking about the Nobel Prize. Suddenly, there is not a unicellular organism, but a multicellular organism. To explain it, Ira immediately comes up with the explanation that the cells are evolving.
Wayne fails his fire brigade exam because he's sleeping, he hits himself in his privates with the hose pipe. He can take the exam again in six months.
Harry and Ira take their classes to see the meteor. There, there is a bad smelling vapour around everywhere, and mushroom-like yellowy things have sprouted out from the floor of the cave. Nadine complains of feeling something on her toes. Under the mist, there are millions of slimy worms. Ira picks one up and it dies when he lifts it up: he thinks that oxygen killed it. Ira puts one in a specimen jar, and it splits over and over again. Ira wants to keep everything secret, because the government will take things from them. Ira seems to know a lot about how the government works.
Wayne is the pool manager, and he's told off about a damp towel by Barry Cartwright (Gregory Itzin). He goes to get some cleaning stuff, and he finds loads of slimy worms on the floor - he stumps on some of them - and wonders at what is inside a kind of container with water - a kind of fish with sharp teeth and bad-ass attitude. He leaves the storeroom. Harry has analyzed the samples and found three different subspecies, the worms are evolving really quickly. They again visit the crash site, but the military are already there. The guard at the gate (Timothy R. Layton) won't let them pass, he enquires about them. Another soldier tries to shoot Ira. They are let in eventually.
There, they meet General Russell Woodman (Ted Levine), Ira's ex-boss, who says that they have been monitoring Ira's computer, and Allison Reed (Julianne Moore), a clumsy scientist who trips on the step and falls down. Harry and Ira see her underwear and make comments about her garter belt. The Army is going to lead the investigation. Ira and Harry have to leave, and Ira moons.
Two weeks later
Ira goes to court to be allowed to be part of the federal investigation. Judge Guilder (Steven Gilborn) gets annoyed when Russell says that Glen Canyon Community College facilities are a joke. Allison questions Ira as a witness. He was dismissed because he gave an experimental anthrax vaccine to soldiers with horrible consequences. They have no chance of winning. When they return to their lab, all the samples and their computer have been stolen in a break in. They get angry so they decide to break in the military facilities, Ira dressed as a colonel and Harry as a soldier.
Inside the facility, they see a large flying mosquito. Lt. Cryer wonders who these two people are - one of them is kinda dancing in the lift. Inside the cave, there is an Alice-in-Wonderland kind of rainforest. Cryer tells Reed of the unauthorized walk through. Colonel Flemming (Ty Burrell) smiles at Harry's sexual comments. A fly has entered Harry's suit. They try to kill it, but it's in his leg. Immediately taken to hospital, Dr. Paulson (Wayne Duvall) removes the bug via Harry's rectum, while nurse Tate (Wendy Braun), Ira and Allison cheer him. When they take the bug out and it breathes oxygen, it dies.
Wayne is the waiter at a party, still pissed off abut his failure. Barry sets a date with a pretty lady at a lonely location at the golf club and a kind of alligator eats him. Wayne isn't sorry at all. Wayne takes the late alligator to Ira and Harry, just out from hospital. It just died choking because of the oxygen in the air.
At a meeting of ladies, at Jill Mason's home (Stephanie Hodge), Patty (Kristen Meadows) finds many dead bugs. Something is pushing a locked door, and Jill makes Grace (Miriam Flynn) open the door. A huge frog-like thing appears. It looks sad and meek. Grace wants to pet it, but alien-like inner mandibles spring out and bite her hands. The ladies panic, and Debbi (Winifred Freedman) tries to call 911, while Jill tries to shoot the animal. However, it chokes to death and deflates.
Ira talks to Allison, saying that they're spreading and adapting. Harry, Wayne and Ira talk over breakfast about the alien. Ira asks Denise (Sarah Silverman), his ex-girlfriend, for some cream. She's with Sam at that moment. Ira reclaims his shirt - which Denise is wearing - so she offers to take it off right there. Sam avoids it, but has to run to work, because he's been called.
The three of them go to check the animal, and Sam lets them. Wayne finds the place where hundreds of alien animals are dying. One big animal dies on the spot, but it gives birth to a small dragon-like animal through the mouth. It immediately flies off to Tumbleweed's, the nearby shopping centre. The three friends steal weapons to shoot it. A middle-aged couple (Mary Pat Gleason & Tony Mirzoian) are the first ones to spot it when it flies through the shop window. A girl (Morgan Nagler) is in the dressing room. The dragon takes her. Wayne sings to attract the dragon. Incredibly enough, the dragon responds to the bad singing, because it looks like it hurts it. Harry takes the girl and Harry shoots the dragon. Everybody claps. The three friends leave by car, dancing to the song Play That Funky Music White Boy
A reporter (Steve Kehela) is reporting on the dozens of dead animals. They interview a road worker (Andrew Bowen) who has a hurt hand, and another reporter (Lee Garlington) says that there are no comments from the government.
Governor Lewis (Dan Aykroyd) is angry at not being informed about the alien situation earlier. The three men interrupt the meeting in which the spread of the aliens is being discussed. Woodman wants to drop an h-bomb onto the things. In the cave, the aliens have evolved into primates which are disabling all cameras, and appear to be leaving through the lift, which is empty, and at that moment lights turn off and the primates attack everybody. One jumps back down the hole through which they appeared, Wayne kills the last one.
Lewis gives Woodman the power to use the bomb. Allison disagrees with Woodman's decision, who makes them leave, but this time, Allison leaves with them. They try to evacuate everybody. Ira addresses a bowl of liquid from the meteor. Harry smokes and throws a match which lands in the liquid, igniting it, causing it to grow immediately, like an indoor firework. Allison tries to tell Woodman not to use the bomb. Deke and Danny take beers to everybody. By looking at the periodic table printed on Allison's T shirt they calculate they need selenium, and a lot of it. The Donalds will create it from Head & Shoulders shampoo, whose active ingredient is selenium sulphide. Wayne borrows the fire-brigade's lorry.
The army and Lewis shoot the aliens, and with the explosions, they expand rapidly. A gigantic worm destroys houses and roads and stomps on soldiers. The huge thing starts dividing. They drive the fire truck under the thing, which nastily farts. Harry introduces a hose pipe as though it were an enema. The thing takes Harry inside, and then, when Harry is out and the truck is driving away, it explodes all over the place, sowing green goo everywhere.
Ira and Allison kiss, covered in green goo. Woodman fights the people who try to clean him up. Lewis congratulates the group. Wayne becomes a firefighter. Allison and Ira go to the fire truck to make love, so they don't take their medals.
The dragon-like animal flies over the three friends because... they are making a commercial for Head & Shoulders shampoo.