Father Costigan discovers that his collection of photographs is mysteriously burning in a selective manner. As he examines the remnants, he realizes they form a disturbing pattern resembling an upside-down sickle, marked with a cross. This unusual symbol is recognized as the inverse of the astrological emblem for Ceres, traditionally representing maternal affection; however, its inversion in this story is perceived by some as a Satanic emblem.
Meanwhile, in Concepción, Chile, Katherine Winter (Hilary Swank) and her colleague Ben (Idris Elba) delve into reports of a supposed miracle. Their investigation uncovers a hidden stash of hazardous waste in a leaking underground oil well, poisoning the local population and causing the bizarre effects attributed to the "miracle."
Upon returning to Louisiana, Katherine receives a dire warning from Father Costigan, revealing that it was her visage aflame in his photos—a sign from God. Dismissing the forewarning, Katherine becomes embroiled in the plight of Doug (David Morrissey), a science teacher from Haven, who seeks her help in deciphering the mystery of the local river turning a vivid red (the first plague). The townsfolk suspect that a twelve-year-old girl, who witnessed her brother's tragic death, is the cause behind this plague. Doug informs Katherine that this girl resides in an area deserted by many after a string of hurricanes devastated the town.
Eager to seek answers, Katherine, alongside Ben, investigates the river and submits water samples for analysis. During their time in the town, Katherine meets Loren McConnell (AnnaSophia Robb) and they witness the peculiar phenomenon of dead frogs cascading from the trees (the second plague). That evening, their meals are plagued by an invasion of flies (the fourth plague), and a contagion (the fifth plague) decimates the livestock of Jim Wakeman (David Jensen).
With no local accommodations, Doug kindly invites them to spend the night at his home. While there, the power unexpectedly fails, leading Katherine to find Doug at his wife's grave. They share personal stories, where Doug encourages Katherine to partake of the local spirits. Katherine recounts her painful past as an ordained minister; she embarked on a humanitarian mission to Sudan with her husband and daughter, but after a year-long drought, locals made a tragic sacrifice of her family to entice rain, shattering Katherine's faith.
In a moment of emotional vulnerability, Katherine and Doug succumb to their mutual attraction and share an intimate encounter. As passion ignites, visions of Loren and Katherine's own haunting memories plague her mind.
The following day, Katherine ventures alone to the McConnells' home, where she stumbles upon cult symbols carved into the walls. A chilling encounter unfolds with Loren's mother, who begs Katherine to end her daughter's life and is subsequently attacked by Loren, urging Katherine to leave. Meanwhile, Ben and Doug uncover the existence of the cult. Shortly thereafter, the water sample results reveal that the river is tainted with human blood. The townspeople, escalating into a frenzy, begin shaving their children's heads due to a lice outbreak (the third plague). Katherine steadfastly insists on a scientific rationale behind these events, attempting to quell the townsfolk's thirst for violence against Loren.
Ben and Doug plead with the mayor to evacuate, but their efforts are thwarted when the mayor and his aides suffer from boils (the sixth plague). In a moment of desperation, Katherine reaches out to Father Costigan, who expresses that the symbol he observed signifies a Satanic cult that conducts sacrifices of every second-born child in pursuit of a "perfect child" imbued with power. He warns Katherine that Loren is this "perfect child" and that she is the angel destined to eliminate the cult. Just as he reveals this, supernatural flames engulf his room, claiming his life.
Unwilling to abandon her search for logic, Katherine returns to the McConnell household alone, uncovering the sacrificial chamber and the cult's symbols in the basement. Loren's mother reveals the dark truth—that "he controls her [Loren] now"—before taking her own life. Loren confronts Katherine, but their exchange is interrupted by the townsfolk's arrival.
As the sheriff and enraged residents of the town prepare to enact vengeance on Loren, a swarm of locusts descends upon them (the eighth plague), seemingly under Loren's sway, wreaking havoc. The unbearable signs lead Katherine to contemplate the supernatural origins of the plagues and her obligation to protect Loren rather than harm her. With the townsfolk encroaching, Doug pressures Katherine into an impossible decision: kill Loren or face doom. Katherine remains resolute, believing this is God's will for her and Loren.
The townsfolk, having long forsaken their faith after hardship befell them, had sought Katherine's assistance, leaving her in a precarious position. As fire rains from above (the tenth plague), Doug reveals his true colors, seeking to end Loren’s life by using Katherine as a shield. In a moment of divine intervention, Loren manipulates the flames to obliterate Doug, while preserving Katherine.
As the film concludes, Katherine and Loren embark on a new journey together. Katherine expresses her desire to create a family just the two of them, but Loren foresightfully reveals they will soon be three, as she is carrying a child—Katherine's unborn son conceived through Doug. This revelation not only haunts Katherine but also reignites her memories of the traumatic event, leaving her fearful that her child may be the foretold demonic offspring.
