Bethany Sloane, a depressed abortion clinic counselor, attends a service at her Illinois church. Donations are being sought for a campaign to stop a New Jersey hospital from disconnecting the life support of John Doe Jersey, a homeless man who was beaten senseless by the Triplets. Metatron – a seraph and the voice of God – appears in Bethany in a pillar of fire and explains that if Bartleby and Loki succeed in returning to heaven, they will nullify God's word, disprove the fundamental concept of God's omnipotence and cancel all existence. Bethany, helped by two prophets, must stop the angels and save the universe.
Now a target, Bethany is attacked by the Triplets, who are hunted by the two predicted prophets: drug-dealing stoners Jay and Silent Bob. Bethany and the prophets are joined by Rufus, the thirteenth apostle, and Serendipity, the muse of creative inspiration, who now works at a strip club in search of her own inspiration. Azrael summons Golgothan, a vile creature made of human feces, but Bob immobilizes him with aerosol air freshener.
On a train to New Jersey, a drunken Bethany reveals her mission to Bartleby, who attempts to kill her; Bob throws the angels off the train. Bartleby and Loki now realize the consequences of their plan; Loki does not want to participate in the destruction of all existence, but Bartleby remains angry at God for his expulsion and for granting free will to humans while requiring servitude from angels, and decides to continue.
Bethany asks why she was called to save the universe; why can't God just do it himself? Metatron admits that we don't know where God is; he disappeared while visiting New Jersey in human form to play skee ball. The task falls to Bethany because – she now learns – she is the last descendant, the great-great-great-great-great-great-great-great-niece of Jesus.
The group fails to persuade Glick to cancel the celebration; Jay steals one of Glick's golf clubs. Their only remaining option is to keep the angels out of the church; but Azrael and the Triplets trap them in a bar to prevent them. Azrael reveals that he sent the clipping to the angels; he would rather end all existence than spend eternity in hell. Bob kills Azrael with the golf club, which Glick had blessed to improve his game. Bethany blesses the contents of the bar sink and the others drown the triplets in holy water. They rush to the church, where Bartleby kills Glick, his parishioners and various passers-by. When Loki – who is now wingless, and therefore mortal, with a conscience – tries to stop him, Bartleby kills him as well.
Jay attempts to seduce Bethany before the end of all existence; when he mentions John Doe Jersey, Bethany puts it all together. Bethany and Bob run across the street to the hospital, while the others try to block Bartleby's path to the church. Bethany disconnects John's life support system, freeing God, but killing herself. Bartleby reaches the entrance to the church, where he confronts God, manifested in female form; she annihilates him with her voice. Bob arrives with Bethany's lifeless body; God resurrects her and conceives a child – the new last descendant – in her womb. God, Metatron, Rufus and Serendipity return to Heaven, leaving Bethany and the Prophets to reflect on the past and the future.
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