It's year one in the Neolithic era and Zed (JACK BLACK) is a clownish hunter whose behavior doesn't sit well in the eyes of clan leader Marlak (MATTHEW WILLIG). But Zed's more interested in Maya (JUNE DIANE RAPHAEL), and tries to encourage his nerdy gatherer friend Oh (MICHAEL CERA) to put the moves on Eema (JUNO TEMPLE).
Before any of that comes to fruition, however, Zed breaks the rules and eats some fruit from the Forbidden Tree and thus is exiled from the clan. With him accidentally burning down Oh's hut on his way out, the two end up out on their own, traveling the countryside, woods and deserts encountering various Biblical figures.
Among them are quarreling brothers Cain (DAVID CROSS) and Abel (PAUL RUDD), as well as Abraham (HANK AZARIA) who's about to sacrifice his son Isaac (CHRISTOPHER MINTZ-PLASSE), but is interrupted long enough to come up with the idea of circumcision.
When Maya and Eema, along with Marlak and others, are captured by Roman slave traders, including Sargon (VINNIE JONES), Zed and Oh set off a rescue mission of sorts, eventually leading to Sodom where they encounter the likes of the High Priest (OLIVER PLATT) and Princess Inanna (OLIVIA WILDE) who become interested in the now nomadic men for different reasons.