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In the year 10,001 B.C., a caveman (Will) is running away from a dinosaur, and gets in a fight with Wolf. He then encounters a saber-toothed alcoholic Amy Winehouse, who informs him that humans will be extinct on August 29, 2008 (which happened to be the film's opening day), unless somebody returns a crystal skull to its altar.

The film flash-forwards to the present, where Will, the protagonist, apparently dreamt the past sequence. He then figures out that his girlfriend, Amy, had sex with another guy, for he finds Flavor Flav is in his bed with them.

Later that day, Will has a "Super Duper Sweet Sixteen" party at his house, even though he is 25. There are many people at the party, including Juney (a parody of Juno), Dr. Phil, The Jonas Brothers, an off-key Jessica Simpson, Seth and Fogell from Superbad, the kids from High School Musical (Performing a musical song and dance), and Justin Timberlake. Will also notices that Amy brought another guy to his party. While at the party, Calvin attempts to curve a bullet around the room to stop Seth and Fogell from stealing the Alchohol, and accidentally kills Dr. Phil, Anton Chigurh, and Fox in the process.

Later, the room shakes and a bulletin on the radio says that it is the end of the world. Will, Calvin, Lisa, and Juney go outside and find that Hannah Montana has been crushed by a meteor and is repeatedly switching between death and life.

Soon after, a mysterious mist begins to consume the street, and they retreat to a garage for shelter. While they're there they meet the girls from Sex and the City, who say it's "their hideout". Juney fights Carrie Bradshaw for the garage Zohan-style, and wins.

Soon after, Calvin says that he is cold and suggests they take their clothes off. Only the girls take their clothes off and the guys stare in awe. Later, Will has a dream where he is a Jumper, and at the end of the dream, he accidentally gets stabbed by Prince Caspian's sword and says, "It's the guy who ruined Star Wars". After Will's dream, the gang leaves the garage, and later, just after it begins raining disgusting body parts Lisa gets crushed by a meteor. Princess Giselle comes out of a manhole and gets hit by a taxi. Calvin catches her and she immediately falls in love with him.

Later, a tornado occurs and the gang hangs on to parking meters and multiple heroes try to help them, including Iron Man, The Incredible Hulk, and Hellboy, all of which then get hit by cows. Then they see Hancock sleeping on a bench who gets hit by a lamp post. When they find shelter, Calvin gets a call on his "Get Smart" phone from Lisa's mother, who is informed about Lisa's death, and how Calvin has found someone hotter, Princess Giselle. Afterwards, they encounter a cute group of singing chipmunks that suddenly turn rabid, attacking the gang and eat Juney's flesh until she passes out and dies. The chipmunks try to go after the others luckily, Calvin and Will trap them in a garbage can and sufficate them to death.

On their way to the museum to save Amy, they run into Batman, who warns them that they must hurry, for they only have a short time until the world ends. They hijack Speed Racer's car, with Michael Jackson in the trunk, and drive to the museum. When they get there, all the artifacts in the museum come alive, including Kung Fu Panda, Calvin then discovers that Giselle is a transvestite by removing 'his' wig. Kung Fu Panda then kills both of them.

Meanwhile, Will and Amy run into Beowulf, who fights Will in the nude. After Beowulf is defeated, Will and Amy meet Will's father and Will returns the crystal Skull to its altar, averting further destruction.

The film ends with a wedding ceremony for Will and Amy being performed by The Guru Shitka. Then all the characters come back to life and sing a song about dating each other (spoofing the "I'm F***ing Matt Damon" song by Sarah Silverman), ending with the chipmunks being crushed by yet another cow.