Bethany (LINDA FIORENTINO) is a woman's clinic employee and practicing Catholic whose turn in life has caused her to question her belief in God. Thus, she's rather surprised when Metatron (ALAN RICKMAN), an angel serving as the voice of God, approaches her with a holy crusade.
It appears that Cardinal Glick (GEORGE CARLIN), the founder of the Catholicism WOW! movement designed to reinvigorate the Church has unknowingly opened a celestial loophole that two fallen angels, Bartleby (BEN AFFLECK) and Loki (MATT DAMON), the angel of death, plan to use to return to Heaven. By doing so, they would prove God fallible and thus wipe out all existence.
Although initially skeptical, Bethany agrees to head off to Glick's New Jersey church. Along the way she picks up the two "prophets" Metatron had promised would assist her, Jay (JASON MEWES), a long- haired, profanity spewing dude who wants to get into bed with Bethany, and Silent Bob (KEVIN SMITH), who barely utters any words. They then pick up Rufus (CHRIS ROCK), the forgotten and disgruntled 13th apostle, as well as Serendipity (SALMA HAYEK), a muse posing as a stripper.
As Bethany and her ragtag group head off on their road trip, they must contend with Azrael (JASON LEE), a demon who, with the help of his street hockey thugs, wants to aid the fallen angels and thus get revenge on God (ALANIS MORISSETTE), who's now missing. With the disillusioned Loki and Bartleby bringing havoc to the sinners of the world as they head from Wisconsin to New Jersey, Bethany and her team try to stop them from passing through Glick's church doors and thus negating everything and everyone in the world.