Zed (Jack Black) is a hunter and Oh (Michael Cera) is a gatherer. After being informed that Zed ate from the Tree of Knowledge of Good and Evil, the shaman (Bill Hader) and Marlak (Matthew Willig) banish him from the tribe. His hut destroyed after Zed burns the village down by accident, Oh reluctantly joins Zed on his journey to discover all the world has to offer. Along the way, they encounter Cain and Abel (David Cross and Paul Rudd). Cain kills Abel with a boulder in an act of rage and informs Zed and Oh that they must escape with him or else he will be accused of killing Abel.
Afterwards, Zed and Oh find that the girls they want to "lay with", Maya (June Diane Raphael) and Eema (Juno Temple), from their former tribe have been captured and are being sold into slavery. They try to buy the girls' freedom, but end up being sold as slaves themselves, as Cain had been looking for a way to rid himself of his murder's witnesses. Whilst in transport, the slave caravan containing Oh, Zed, Maya, Eema and others from their tribe is attacked and overpowered by Sodomites, though Zed and Oh successfully escape and hide in the desert but lose track of the now Sodomite-led slave caravan.
Still resolved to free the slaves and knowing the new destination of the caravan, Zed and Oh determinedly journey on and pass by a mountain where they find Abraham (Hank Azaria) about to kill his son Isaac (Christopher Mintz-Plasse). Zed stops them, letting Abraham believe Abraham's Deity sent him to do so. Abraham takes them to his Hebrew village and tells them about the cities of Sodom and Gomorrah.
Zed and Oh head off for Sodom after Abraham decides to circumcise them. As they arrive in Sodom, they are captured. Cain, now a Sodomite soldier, saves them from being sodomized, calling them his "brothers". The two recalled that they were sold by Cain as slaves and Cain apologizes and offers them food. While being given a tour of the city by Cain, Zed and Oh are offered by Cain to become guards. Shortly after they become guards and are patrolling the city they see the princess Inanna (Olivia Wilde), who is fasting because she feels guilty that most of the city is starving. Inanna notices (and is herself inspired by) Zed and has him invited to a party that night, from which she has him surreptitiously pulled aside for clandestine discussion.
Inside the palace, Zed sees Maya and Eema serving as slaves, but Oh is forced to follow the very effeminate High Priest around the palace while Zed meets with Princess Inanna, who asks him to enter the Holy of Holies and tell her what it is like, thinking that Zed is the "Chosen One". Inside the temple, Zed encounters Oh, who is hiding from the high priest (Oliver Platt). There, they get into a heated argument and are ratted on by an eavesdropping Cain, then imprisoned for going inside the temple. The two are sentenced to be stoned to death but Zed convinces the Sodomites to have mercy, so they are instead sentenced to hard labor until they die from work. The king then announces that he will be sacrificing his daughter and two virgins (Maya and Eema), who were also ratted out by Cain as "followers of the Chosen One" as a gift to the gods. The growing crowd, already at its breaking point from the famine, reacts negatively as Princess Inanna is already very popular for her regular displays of solidarity with the people, who would be losing an important ally from within the King's Court if she were removed.
Zed interrupts the ceremony and Oh instigates a riot with the exclamation "The Chosen One Comes"! Abraham arrives with the Hebrews to help overthrow the King. Oh and Eema lie with each other inside the palace, which not only consummates their relationship, but also means that Eema cannot be sacrificed. They then come out to help Zed subdue the other soldiers, who have already turned on and killed the King, and together Zed and Oh also stop the High Priest from sacrificing Maya. The crowd is ready to proclaim Zed as the Leader being the "Chosen One" but Zed, though initially caught up in the moment, sees the expressions of his sister and best friend, now a couple (a pairing Zed had long hoped for), and belatedly recalls that his love for them and Maya far outstrips his desire of a Savior persona. Instead, Zed lets a personally grateful Inanna rule, and becomes an explorer with Maya (and expresses his sincere and profound gratitude for her companionship). Oh becomes the leader of the village where the whole adventure started. The two say their goodbyes, and head their separate ways.
Jack Black as Zed, son of Zero
Michael Cera as Oh, son of Ooh
Olivia Wilde as Princess Inanna[3]
June Diane Raphael as Maya
David Cross as Cain
Gabriel Sunday as Seth
Paul Rudd as Abel[4] (uncredited)
Juno Temple as Eema, daughter of Zero and sister of Zed
Matthew J. Willig as Marlak
Horatio Sanz as Enmebaragesi
Oliver Platt as High Priest
Christopher Mintz-Plasse as Isaac
Eden Riegel as Lilith
Hank Azaria as Abraham
Bill Hader as The Shaman
Vinnie Jones as Sargon
Harold Ramis as Adam
Rhoda Griffis as Eve
Xander Berkeley as The King
Gia Carides as The Queen
Paul Scheer as Bricklayer
David Pasquesi as Prime Minister
Kyle Gass as Zaftig the Eunuch
Marshall Manesh as Slave Trader
Bryan Massey as New Guard