Jesse, Tulip and Cassidy race down a Texas highway in search of God. Jesse uses Genesis to evade arrest from cops who pull them over for speeding. The Saint of Killers tracks them and guns down all the cops. Jesse, Tulip and Cassidy escape.
Jesse and Co. pay a visit to Jesse’s preacher friend, Mike, who says that God reportedly stopped by the strip club of one of his parishioners, Tammy. The Saint later shows up at Mike’s house looking for Jesse. Mike kills himself before the Saint can force him to give up Jesse’s destination.
Tammy informs Jesse that God visited the strip club to listen to jazz.
The Saint, who tracks Jesse whenever he uses Genesis, attacks Jesse outside his motel. Jesse tries to use Genesis against the Saint but it doesn’t work. Jesse, Tulip and Cassidy flee. Cassidy suggests they seek help from the angel Fiore, who he recently learned is working as the Amazing Ganesh at the Mumbai Sky Tower.
Fiore tells Jesse that he has the power to call off the Saint but refuses to help Jesse in his search for God. Cassidy convinces Fiore to call off the Saint by treating him to a drug-fueled romp. However, Fiore later changes his mind and orders the Saint to pursue Jesse in New Orleans.
Jesse and Tulip decide to get married. Tulip is spotted by a former associate, Gary, and she kills him before he can call his boss, Viktor. She changes her mind about getting married.
In a flashback, Eugene talks Tracy Loach out of killing herself after she learns that her boyfriend cheated on her. She recoils when he tries to kiss her then shoots herself after all. Eugene shoots himself. In Hell, Eugene stands in a locked cell and watches the scene on a loop.
Jesse, Tulip, and Cassidy look for God in a New Orleans jazz club. A bouncer leads them to a man in a dog costume, ready to perform a kinky sex act. Cassidy and Tulip retire to the apartment of Cassidy’s friend Denis. Tulip confesses to Cassidy that she’s in trouble with a man named Viktor.
Jesse meets a lounge singer, Lara Featherstone, and informs her that he’s looking for God. Jesse uses Genesis to save Lara from a band of men in white suits. Featherstone later removes her wig and joins the men in white. She orders them to send Jesse’s case up to the Samson Unit. Jesse’s file arrives at the desk of Herr K. Starr, the leader of the Samson Unit.
In Hell, Eugene meets Adolf Hitler and watches Hitler’s Hell memory: a failed date with a woman in Munich.
While watching an informercial, Cassidy recognizes one of the actors as God from Jesse’s phone call to Heaven. Jesse and Cassidy obtain the actor’s God audition tape and see someone shoot the actor dead.
Eugene and others from his cell block are sent to a holding cell in Hell while the projectors in their cells are fixed.
Viktor’s thugs abduct Tulip and bring her to Viktor’s mansion. Worried about Tulip’s long absence, Cassidy tells Jesse about Viktor. Jesse storms Viktor’s mansion only to learn that Tulip is married to Viktor. Viktor agrees to divorce Tulip.
In a flashback, Tulip and Jesse attempt to live a normal life after Tulip’s miscarriage. Jesse discovers that Tulip has secretly begun working for Dany again and is also taking birth control, thwarting their attempts to have another baby. He leaves her to become a preacher in Annville. Tulip meets Viktor and marries him, but abandons him to seek vengeance against Carlos.
The Saint goes to Viktor’s mansion in search of Jesse and kills Viktor. Allie, Viktor’s daughter, leads the Saint to Denis’ apartment complex. Jesse’s group escapes just in time. They research the Saint and learn that he is the only living man without a soul. Jesse tells the Saint that he has the power to send him to Heaven. The Saint takes Tulip, Cassidy and Denis hostage and gives Jesse one hour to get him into Heaven. Cassidy reveals to Tulip that Denis is his son. Tulip asks the Saint to release Denis, who is growing sick, but the Saint hurls her to the ground.
Jesse asks a technician for Soul Happy Go Go, a soul-extracting company, to find a soul for the Saint. The technician discovers that Jesse’s own soul is a match and extracts 1 percent of Jesse’s soul. Jesse gives a pill containing his soul to the Saint then commands the Saint to get on his knees, explaining that the Saint is no longer immune to Genesis because he now has a soul. Jesse puts the Saint in a Soul Happy Go Go armored vehicle and sends it into a swamp. He hides the Saint’s weapons underneath the floor tiles in Denis’s bathroom.
Jesse’s gang takes a break from their God search and scams patrons at the Hurt Locker bar, where bulletproof-vested patrons shoot each other for fun. Jesse assures a rattled Tulip that the Saint is gone.
Denis tells Cassidy that he’s dying of a heart disease and begs him to help him become immortal. Cassidy refuses.
Flash back to 2004: Herr Starr wins a series of competitions to become the newest agent of the Grail. A Grail agent named Saltonstall informs Herr Starr that the Grail has protected Jesus’s heirs in preparation for the end of the world. Herr Starr kills Saltonstall and takes over his position as head of the Samson Unit.
Tulip tries to overcome her fear of the Saint by repeatedly visiting the Hurt Locker and imagining the Saint as her shooter.
Featherstone and her partner, Hoover, stake out Jesse & Co. in an apartment down the hall from Denis and watch footage from surveillance cameras hidden in Denis’s apartment.
Superintendent Mannering realizes that there’s an impostor in Hell and vows to find out who it is. Hitler offers to help Eugene escape before Mannering discovers he’s the impostor. To give Eugene a taste of Mannering’s punishment, Hitler tricks Eugene into being nice in front of Mannering, who promptly sends him to the Hole for his good deed. In the Hole, a projector replays Eugene’s worst memory with Tracy and changes the story to make it even worse.
As Denis’s health worsens, Cassidy finally agrees to bite him and turn him into a vampire.
Tulip meets Featherstone, who introduces herself as “Jenny.”
Starr is unimpressed by footage of Jesse’s power and orders Featherstone to kill Jesse and his friends. He later changes his mind and introduces himself to Jesse, revealing that the Grail covered up God’s disappearance. He explains that the Grail has protected Christ’s lineage in preparation for the end of the world, at which point the Messiah — Jesus’s 25th great-grandson — will reveal himself. He brings Jesse to the Messiah, who turns out to be an inbred simpleton named Humperdoo. Jesse sees drawings of dogs on Humperdoo’s desk.
Cassidy and Denis take dates to an arcade. Cassidy admonishes Denis for biting his date and warns him against acting on his new appetites.
Tulip and Featherstone play video games at Denis’ apartment. Featherstone speaks enviously of Tulip’s life of robbing banks in Dallas and looking for God. Tulip says she never told Featherstone about Dallas and demands to know Featherstone’s true identity. Featherstone secretly calls Hoover. Moments later, Hoover pretends to be “Rodney,” the abusive ex of “Jenny,” Featherstone’s cover identity. Tulip and Featherstone beat him up.
Tulip discovers the Saint’s weapons and yells at Jesse for lying to her about the Saint. They recover the armored vehicle from the swamp but find it empty. Tulip tries to melt the Saint’s weapons but the weapons prove impervious to molten metal. She sends the weapons to Brazil.
Starr proposes that Jesse fill the vacuum left by God. Jesse accuses him of blasphemy.
Jesse connects Humperdoo’s dog drawings with the Man Dog at the jazz bar. When he returns to the jazz bar, however, Man Dog is gone.
Mannering summons Eugene to determine whether he is the Hell impostor. Hitler distracts Mannering and shows Eugene an escape route. Eugene unlocks the secret door out of prison by standing up for himself in his Tracy Loach memory. He escapes with Hitler.
Starr implores Jesse to take over for God but Jesse again refuses. Upon Starr’s instruction, Hoover visits the Saint in the Soul Happy Go Go vehicle, which the Grail recovered from the swamp and replaced with a decoy. Hoover convinces the Saint to make a deal with the Grail then releases him to go after Jesse.
The Saint shows up at Denis’s apartment. Jesse tries to stop him but Genesis no longer works. As the Saint prepares to scalp Jesse, Mannering arrives to bring the Saint back to Hell on Starr’s orders.
Starr brings Tulip and Cassidy to his office and tells them that Jesse is destined for greatness. Tulip and Cassidy confront Jesse about his dealings with the Grail. Jesse reasons that he has no choice but to take over for God, with Humperdoo next in line. They refuse to join him.
In 1994, a teenage Jesse greets tourists at Angelville, where people have come to see his grandmother Madame L’Angelle, a “world-renowned spiritist.” He pickpockets their wallets and gives the money to Madame L’Angelle’s men. When Jesse kills a chicken in anger, he asks Madame L’Angelle to revive it.
In the present, Jesse reads his first speech as Messiah to a classroom of young children. A band of armed Armenians storm the classroom. Starr films Jesse as he defeats the assailants. The video goes viral. Starr admits that he staged the attack to get Jesse’s name out quickly.
Tulip discovers a spy camera in the apartment and realizes the Grail has been spying on them.
Eugene and Hitler escape the prison and arrive at the River Styx. Mannering shoots the ferryman with an arrow. Hitler knocks her unconscious then joins Eugene in the ferry. After they escape Hell, Hitler bolts. Eugene realizes what he’s just unleashed on the world.
Cassidy fantasizes about kissing Tulip and biting her. Denis leers at Tulip’s lingerie in the laundry and encourages Cassidy to go after her. Cassidy pushes him onto the sunny terrace and burns him to death to rid himself of Denis’s bad influence.
Tulip goes to “Jenny’s” apartment and notices a “Soul Happy Go Go How-To Extraction Manual.” Realizing that her cover is blown, Featherstone whips out her gun and shoots Tulip. Jesse abandons his Messiah tour to rush to Denis’s apartment, where Tulip is dying from a gunshot wound. Cassidy tries to bite her but Jesse fights him off and insists they let her die.
Jesse and Cassidy drive to Angelville with Tulip’s dead body. Cassidy tells Jesse that he has hated him for a long time.
God stays at a motel. His Man Dog costume hangs in his room.