The story begins in the Sola Mira Hive, where the valiant trio of Priest (Paul Bettany), Priestess (Maggie Q), and the villainous Black Hat (Karl Urban) are on a mission to hunt down vampires. However, they soon fall into a perilous trap that leads to Black Hat's capture by these bloodthirsty creatures.
A fascinating animated segment unfolds, depicting the relentless battle between man and vampire, showcasing the devastation they wreak upon one another and their environment. In a bid for survival, humanity retreats behind the protective walls of the church, relying on priests—extraordinarily skilled men—to defend them. But after the vampires are vanquished, the priests are sent back to live among the populace, their services no longer deemed necessary.
In the desolate wasteland, we meet Owen Pace (Stephen Moyer), who is striving to cultivate a farm alongside his beloved wife Shannon (Madchen Amick) and their daughter Lucy (Lily Collins). The harsh environment is daunting, yet Owen clings to the hope that radiation levels will soon drop enough for them to successfully grow crops. Lucy, however, feels stifled in their sheltered life. Their tranquility is abruptly shattered when a gang of vampires assault their home, resulting in Owen sustaining injuries while Shannon tragically loses her life, leaving Lucy in a state of panic.
Venturing into the advanced Cathedral City, the public receives broadcast messages from Monsignor Orelas (Christopher Plummer), while Priest meanders through the bustling streets. During a confession, he realizes that the guidance offered is merely a recording. Later, Hicks (Cam Gigandet) approaches Priest with alarming news about his brother Owen's attack and implores him to help confront the vampires. Seeking permission to pursue this dark threat, Priest heads to the church, only to be met with skepticism from Orelas, who dismisses the notion of vampires and cautions Priest against questioning the church's fundamental beliefs. Undeterred, Priest defies his vows.
Meanwhile, Lucy finds herself imprisoned aboard a train with Black Hat as her captor. Fueled by determination, Priest equips himself and sets off on a high-tech motorcycle towards the wasteland. Arriving at Owen’s farm, he reunites with Hicks, who fervently asks Priest to rescue Lucy and eliminate all vampires lurking in the shadows.
In a race against time, Monsignor Orelas dispatches a group of priests to either capture or eliminate Priest. Taking matters into his own hands, Priest starts his hunt for the vampires, leading him and Hicks to what appears to be a deserted vampire reservation. The guards are missing, and upon venturing further into the underground hive, they discover the carnage left behind. A sudden attack by the familiars ensues, and Priest fights them off valiantly. As night falls, the true horror begins to unfold with the awakening of the vampires. They desperately fend off the onslaught, managing to extract crucial information about Lucy's fate, confirming she has been taken west to the Sola Mira Hive.
One of Black Hat's informants betrays him, revealing the actions of Priest and Hicks. Arriving at the Hive brings back haunting memories for Priest. He parts ways with Hicks at the entrance and delves deeper into the hive. There, he reunites with the Priestess, and together they confront a formidable hive guardian, whose defeat comes with the help of Hicks. They discover that Black Hat's army is wreaking havoc in the town of Jericho, escalating their urgency to thwart the impending slaughter.
When Priest, Hicks, and the Priestess eventually reach the town, they find it chillingly abandoned, with the church priests gruesomely crucified. Realization dawns on Priest that the vampires are now heading towards the city. They strategize to intercept Black Hat’s train, intending to free Lucy while thwarting the vampire menace. In a poignant moment, Priestess gives Priest a unique cross before they set off on their mission.
As they race towards the train, Hicks learns about Lucy’s true lineage—she is Priest's daughter. Joining forces on the train, they execute their plan, but disaster strikes when Priestess's explosives are deactivated, sabotaged by a familiar. Hicks bravely battles through the vampires to reach Lucy, and as the action escalates, Black Hat confronts Priest, revealing his transformation into a human vampire through the Queen’s blood, making him far more powerful than Priest.
Just when it seems that defeat is imminent, Priestess bravely arms the explosives once more while racing towards the train. Meanwhile, Priest uses the special cross against Black Hat to save Lucy, leading to an explosive climax as Priestess detonates the bomb, obliterating the train.
In the aftermath, Hicks discovers Priest safely cradling Lucy, who learns of their familial bond. Together with Priestess, the trio emerges from the chaos, ready to face the future. Returning to the church, Priest boldly throws a vampire head at Orelas' feet, proclaiming that the battle against the vampires has only just begun. He then reunites with Priestess, as they continue their relentless quest to hunt down the darkness that threatens their world.
