In the year 10,001 B.C., a caveman runs away from a predator through a plain and immediately gets into a fight with Wolf (Ike Barinholtz). After defeating him, the caveman then encounters the predator, a saber-toothed, gasoline-drinking Amy Winehouse (Nicole Parker), who informs him that the world will end on August 29, 2008 and that their fate lies in a Crystal Skull. The sequence is then revealed to be a dream of Will (Matt Lanter) in the present day. He then finds out that his girlfriend Amy (Vanessa Minnillo) is having an affair with Flavor Flav (Abe Spigner), and she breaks up with Will because he is not admitting his true feelings for her.
Later that day, Will has a "Super Duper Sweet Sixteen" party at his house, despite being 25. The guests include Juney (Crista Flanagan), Dr. Phil (John Di Domenico), Will's best friend Calvin (Gary "G Thang" Johnson), and Anton Chigurh (Barinholtz), among others. During the party, Amy arrives with her new boyfriend, a Calvin Klein underwear model. The party then comes to a halt when the room shakes and the lights go out. A bulletin on the radio claims there is a meteor shower and it is the end of the world. Soon after, the city starts to freeze over, and Will, Juney, Calvin, and Calvin's girlfriend Lisa retreat to a garage for shelter. When Juney mentions that the calamities are caused by global warming, Will realizes his dream about Amy Winehouse could be related. Later, Will is chided by the others for not committing himself to his relationship with Amy.
The gang leaves the garage and Will gets a call from Amy, where he admits his feelings for her before the call is dropped. He decides to go to rescue Amy. Lisa is later killed by a meteor. While the others comfort a distraught Calvin, the Enchanted Princess (Parker), a prostitute, climbs out of a manhole and gets hit by a taxi. Calvin catches her, and they immediately fall in love with each other. The Princess' pimp, Prince Edwin (Tad Hilgenbrink), challenges Calvin to a dance fight for her love, but a tornado appears and Prince Edwin escapes. Iron Man (Gerrard Fachinni), Hellboy (Barinholtz), and the Hulk (Roland Kickinger) attempt to fight it, but all are defeated by cows thrown by the tornado. After taking shelter, Will, Juney, Calvin, and the Princess encounter rabid knockoffs of Alvin and the Chipmunks, who attack the gang and kill Juney. The Chipmunks then go after Will and Calvin, but they trap them in a trash can, fatally suffocating them as they attempt to escape.
On their way to the museum Amy is trapped, the group runs into Batman, who informs them that they must go to evacuation buses and that there will be no chance of survival if they go to save Amy. With time against them, the Princess Giselle kills Speed Racer (Jared S. Eddo), and the group hijacks his Mach Five to drive to the museum. At the museum, they save Amy, who reveals that the Crystal Skull is the only thing that can stop the end of the world. Calvin and the Princess then find that the museum doors are closed and all of the artifacts have come alive, including Kung Fu Panda (Yoshio Iizuka), who fights Calvin but is defeated. When Calvin makes out with the Princess, Calvin accidentally pulls her wig and discovers that she is actually a transvestite. While this happens, Kung Fu Panda takes out a katana and kills Calvin and the Princess.
Meanwhile, Will and Amy run into a nude Beowulf (Barinholtz), who fights with Will. After Beowulf is defeated, Will and Amy encounter Indiana Jones (Tony Cox), who is revealed to be Will's father. Indy tries to put the Crystal Skull on the altar, but he has an accident. Will does it instead, and he averts further destruction. The film ends with a wedding ceremony for Will and Amy being performed by The Guru Shitka (Domenico). The film ends with an extensive musical number about all of the characters dating each other, which sets off a chain, ending with the Chipmunks.
What's the only thing that can stop the end of the world
Crystal Skull