Ten years after the first American Pie movie, three new hapless virgins discover the Bible hidden in the school library at East Great Falls High. Unfortunately for them, the book is ruined, and with incomplete advice, the Bible leads them on a hilarious journey to lose their virginity.
A fanatical animal rights activist releases giant pythons into the Everglades, believing the wild animals should be set free. When they start decimating the native animal population, an over-zealous park ranger feeds experimental steroids to wild alligators so they can fight back. The giant pythons and gargantuan alligators go on a killing spree, and it is now left up to the two feuding women to put aside their differences to put a stop to the creatures and the destruction.