In Annville, Texas, local preacher Jesse Custer delivers an uninspired sermon to a bored congregation. A young boy asks Jesse to hurt his father, Donnie, for abusing his mother. Jesse refuses but checks in on Donnie’s wife, Betsy.
In a corporate jet, an Irish vampire named Cassidy drinks and snorts cocaine with a group of hedge funders but kills them after learning they’re assassins there to take him out. He jumps out of the plane and lands near Annville.
Jesse’s assistant, Emily Woodrow, warns Jesse about the church’s precarious finances.
Tulip O’Hare kills a gangster and snatches a map from his jacket. She tracks Jesse down in Annville and invites him to help with a job, but Jesse refuses.
In a flashback, a young Jesse is forced to watch as men shoot his father, John Custer, in the head. Before his father dies, Jesse promises to be one of the good guys.
Jesse visits Eugene Root, a severely disfigured teen, to assure him that God still loves him, despite whatever he’s done wrong.
Cassidy meets Jesse at a local bar. Jesse beats up Donnie after Donnie confronts him for talking to Betsy. Sheriff Hugo Root arrests Jesse and Cassidy. The two bond in their jail cell.
At church, the “comet” slams Jesse to the ground, except it doesn’t kill him. Jesse wakes up three days later.
A congregant, Ted, nags Jesse for advice about his difficult mother. “Tell her the truth, open your heart,” Jesse says sternly. Ted immediately goes to his mother’s retirement home, cuts his chest open and removes his heart.
In 1881, a cowboy rides day and night to get medicine for his dying daughter. He arrives in the town of Ratwater.
Back in the present, Jesse vows to be a better preacher and starts to boost church attendance.
Fiore and DeBlanc arrive at the church where Jesse is passed out drunk on the floor. “It’s here,” says DeBlanc. They perform a ritual on Jesse. When that doesn’t work they get a chainsaw ready. Cassidy strolls in with a fresh bottle of whiskey, discovering Fiore and DeBlanc and killing them before they can harm Jesse.
Linus, one of the congregants, confesses to Jesse that he’s attracted to a young girl. Jesse tortures him and orders him to repent. “Forget her,” Jesse bellows. “Forget who?” asks Linus. Realizing he possesses a special power, Jesse visits Tracy Loach, a comatose teenager, and orders her to open her eyes. Tracy opens her eyes.
Jesse tells Cassidy about his new power.
Tulip returns from a trip to Houston and tells Jesse that she procured the address of a man named Carlos. Jesse agrees to help her kill Carlos and they drive off together.
Fiore and DeBlanc re-appear to Cassidy’s amazement. They tell Cassidy that they’re angels from Heaven and that Jesse has something they need back. Cassidy promises to speak with Jesse.
Donnie corners Jesse at a gas station and holds him at gunpoint. Jesse uses his power, the Word of God, to turn the gun around on Donnie and escape. He then changes his mind about Carlos and abandons Tulip.
Mayor Miles Person visits Odin Quincannon, owner of Quincannon Meat & Power, to propose a partnership with the Green Acre group to boost local tax revenues. Quincannon refuses.
Emily sleeps with Miles but emphasizes that she will never be in a relationship with him.
Tulip trades angry words with Clive while lodging at the local whorehouse. She attacks a man who she thinks is Clive but is actually Cassidy. She takes Cassidy to the hospital and is shocked when she finds him recovering, slurping blood in the blood bank.
In a scheme to boost church attendance, Jesse promises to give Quincannon his father’s land if Quincannon, an atheist, does not leave his Sunday service a Christian. At the service, he uses the Word of God and commands Quincannon to serve God. To everyone’s surprise, Quincannon agrees. The spectacle attracts more congregants.
In 1881, the Cowboy picks up his daughter’s medicine at the Ratwater apothecary. Instead of returning home, he tries to save a pioneer family but instead gets beat up by a debauched preacher, who also shoots the Cowboy’s horse. When the Cowboy finally returns home, his wife and daughter are dead.
Cassidy professes his love for Tulip but she says she has a boyfriend. Not too long after, Tulip has a change of heart and has sex with Cassidy.
Using the Word of God, Jesse commands Mrs. Loach, Tracy’s mother, to forgive Eugene.
Quincannon agrees to meet with the Green Acre executives. Before the meeting can start he guns them all down. Miles takes the bodies and stages a car crash to conceal the murder.
Fiore and DeBlanc track down Jesse and tell him he possesses an extremely powerful entity called Genesis. A seraphim tries to report Fiore and DeBlanc for coming to Earth illegally. They kill her and escape with Jesse as the seraphim resurrects in a process called “reinvigoration.”
The seraphim attacks Fiore, DeBlanc, Jesse and Cassidy in a motel room. They dismember the seraphim to keep her from reinvigorating. However, Jesse refuses to give up Genesis.
Cassidy becomes heartbroken upon realizing that Jesse is Tulip’s “boyfriend.”
Eugene tells Jesse that his special power is a form of “cheating.” “Go to hell,” Jesse roars. Eugene disappears on the spot. Cassidy witnesses it all.
In a flashback, John Custer allows a young Tulip to stay with him and Jesse but then calls the Department of Human Services to take her away. “Kill my dad,” Jesse prays angrily. Later that night, a group of men shoot his father dead.
Quincannon orders Jesse to sign a deed and transfer for the church, saying he never became a Christian. Jesse refuses.
Cassidy insists Jesse help find Eugene. Jesse says Eugene is not a saint and better men have gone to Hell. He reveals to Cassidy that Eugene shot Tracy Loach in the head after she rejected him then turned the gun on himself. Cassidy outs himself as a vampire. He gives Jesse a fire extinguisher then steps into the sunlight, causing him to burst into flames.
In a flashback, Quincannon’s entire family dies in a freak accident. Quincannon snaps and calls John Custer in the middle of the night and tells him to denounce God.
In the present, Quincannon leads an attack on the church. Jesse fights back, starting a siege. Jesse summons Fiore and DeBlanc and agrees to return Genesis if they bring Eugene back from Hell. They retrieve Genesis but refuse to help find Eugene. Genesis jumps back into Jesse.
Donnie blows out his ear drums to make himself immune to the Word of God. He ambushes Jesse in the church and knocks him unconscious. Admitting defeat, Jesse asks Quincannon for one more Sunday before signing over the deed. He vows to bring God to Annville and promises to denounce God if the town doesn’t like what he has to say.
Tulip feeds animals to Cassidy to resuscitate him after Jesse nearly let him die burning in the sun. Tulip informs Emily that Cassidy is a vampire and asks her to feed Cassidy the animals while she goes to kill Carlos in Albuquerque. Emily lures Miles to the house and feeds him to Cassidy instead.
Sheriff Root arrests Jesse but Jesse escapes. Jesse steals the Heaven phone from Fiore and DeBlanc and apologizes to Cassidy for letting him burn in the sun.
Fiore and DeBlanc buy tickets to Hell from a travel agent.
Back in 1881, the Cowboy returns to Ratwater and slaughters everyone in town. We relive the Cowboy’s story over and over, from the sick daughter to the massacre only to realize this is Hell. Fiore and DeBlanc arrive and offer to release the Cowboy from Hell if he kills Jesse. The Cowboy kills DeBlanc.
Sheriff Root deduces that Cassidy is a vampire and tortures him to find out what Jesse did with Eugene.
Tulip returns to Annville and dares Jesse to kill a bound-and-gagged Carlos stuffed in her trunk. A flashback reveals that Carlos was Tulip and Jesse’s former partner, who abandoned them in the middle of a bank robbery. The stress caused Tulip to miscarry. Rather than kill Carlos, they brutally beat him up.
At church, Jesse stands before a packed house and calls God with the Heaven phone. God appears and speaks to the audience, but Jesse senses something amiss. The angel pretending to be God finally admits that God is missing. Chaos and depression descend on Annville’s citizens as the news sinks in.
A “danger” sign flashes in a control room at Quincannon Meat & Power. Methane gas blasts out of pipes around town. Some cigarette embers ignite the methane, resulting in a blast that incinerates the town.
Jesse, Cassidy and Tulip, who were eating at a diner outside of Annville, decide to find God.
The Cowboy shows up among the wreckage in Annville. “Preacher,” he growls.