A centuries-long war between humans and vampires has devastated the planet's surface and led to a theocracy under an organization called The Church. They constructed giant walled cities to protect mankind and developed a group of elite warriors, the Priests, to turn the tide against the vampires. The majority of the vampires were killed, while the remainder were placed in reservations. With the war over, the Clergy disbanded the Priests. Outside the walled cities, some humans seek out a living, free from the totalitarian control of the Church.
Priest (Paul Bettany) is approached by Hicks (Cam Gigandet), the sheriff of Augustine, a free town. Priest learns that his brother and his wife, Shannon�Priest's girlfriend before he entered the priesthood�were mortally wounded in a vampire attack, and Priest's niece, Lucy (Lily Collins), was kidnapped. Hicks asks for Priest's help in rescuing Lucy. Priest asks the Clergy to reinstate his authority, but Church leader Monsignor Orelas (Christopher Plummer) does not believe the vampire story and refuses, not wanting to discourage the idea that the Church completely defeated the vampires for fear of compromising their authority over the city. Priest defiantly leaves the city and Orelas sends three Priests and a Priestess to bring him back.
Priest and Hicks arrive at Nightshade Reservation where humans called Familiars, people infected with a pathogen that makes them subservient to the vampires, live alongside a number of the surviving vampires. After a fierce battle, the pair discovers that most of the vampires have taken shelter in Sola Mira, a vampire hive where Priest lost several of his comrades during a major battle. Priestess (Maggie Q) joins them at Sola Mira, revealing a bond with Priest. The trio destroys a Hive Guardian vampire, then discover that the vampires have bred a new army and dug a tunnel out of the mountain towards a town called Jericho. The other three Priests have arrived at Jericho just as night falls and an armored train arrives, unleashing hundreds of vampires upon the population. The vampires are led by a powerful and mysterious human wearing a black hat (Karl Urban). When the three Priests reject Black Hat's offer to join him, he kills them all.
The next morning, Priest, Priestess and Hicks arrive in Jericho and discover the town empty and the three dead Priests crucified. Priest and Priestess share an intimate moment where she makes her move, hoping that now that Shannon has died, he would no longer feel bound to her. Priest, who is clearly not over Shannon, gently refuses. Priest realizes that the vampires have been using the trains to travel by day and attack the free towns by night, with the walled cities at the end of the train line. Hicks believes an attack on the cities would be unwise because of the sun, but Priest reveals that factories, producing massive clouds of smoke and ash, have permanently deprived the city of sunlight, so the vampire attack would be a slaughter.
Hicks threatens Priest, claiming he will shoot him unless he promises to let Lucy live whether she has been infected or not. (Priest had earlier revealed to Hicks, who is in love with Lucy, that if they discovered Lucy had been infected as a Familiar, he would kill her.) Hicks does not understand why Priest, who is basically a stranger to Lucy, cares so much about her. Priestess reveals that Lucy is actually Priest's daughter, and that his brother, Owen, stepped in as a husband and a father when Priest was taken by The Church.
