Bartleby and Loki are fallen angels, eternally banished from heaven to Wisconsin for insubordination, after an inebriated Loki resigned as the Angel of Death. In a newspaper article that arrives anonymously, the angels discover a way home: Cardinal Ignatius Glick is rededicating his church in Red Bank, New Jersey, in the image of the "Buddy Christ". Anyone entering during the rededication festivities will receive a plenary indulgence, remitting all sins. Were the banished angels to undergo this rite and then die after transmuting into human form, God would have no choice but to allow them reentry into Heaven. They are encouraged by the demon Azrael and the Stygian Triplets, three teenage hoodlums who serve Azrael in hell.

Bethany Sloane—a depressed abortion clinic counselor—attends a service at her church in Illinois. Donations are solicited for a campaign to stop a New Jersey hospital from disconnecting life support on John Doe Jersey, a homeless man who was beaten senseless by the Triplets. Metatron—a seraph, and the voice of God—appears to Bethany in a pillar of fire and explains that if Bartleby and Loki succeed in re-entering Heaven, they will overrule the word of God, disprove the fundamental concept of God's omnipotence, and nullify all of existence. Bethany, aided by two prophets, must stop the angels and save the universe.

Now a target, Bethany is attacked by the Triplets, who are driven off by the two foretold 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, now working in a strip club in search of inspiration of her own. Azrael summons the Golgothan—a vile creature made of human excrement—but Bob immobilizes it with aerosol air freshener.

On a train to New Jersey, a drunken Bethany reveals her mission to Bartleby, who tries to kill her; Bob throws the angels off the train. Bartleby and Loki now realize the consequences of their scheme; Loki wants no part of destroying all existence, but Bartleby remains angry at God for his expulsion, and for granting free will to humans while demanding servitude of angels, and resolves to proceed.

Bethany asks why she has been called upon to save the universe; why can't God simply do it himself? Metatron admits that God's whereabouts are unknown; 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 scion, the great-great-great-great-great-great-great-great-grandniece 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 from doing so. Azrael reveals that he sent the news 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 bar sink's contents, and the others drown the Triplets in the holy water. They race to the church, where Bartleby kills Glick, his parishioners, and assorted bystanders. When Loki—who is now wingless, and therefore mortal, with a conscience—attempts to stop him, Bartleby kills him as well.

Jay attempts to seduce Bethany before all existence ends; when he mentions John Doe Jersey, Bethany puts it all together. Bethany and Bob race across the street to the hospital, as the others try to block Bartleby's path to the church. Bethany disconnects John's life support, liberating God, but killing herself. Bartleby reaches the church entrance, 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 scion—within 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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