Marcus, Kristopher Shepard, is a dedicated paramedic whose night takes a dark turn when he becomes emotionally connected to Emma Carillo, Rachel Emmers, a dying patient with five stab wounds. He fights to save her life, but she dies at Mercy Hospital, while Caroline Kuntz, JJ Neward, awakens, murders two people, and vanishes into the night. Marcus’s world begins to unravel as he returns home to find his wife Carla, Ava Gaudet, sleeping with a stranger. He also learns Emma had already died before he attempted her revival, and he is suspended from work for the medical mistreatment and death of a sex worker, Elizabeth Markham. Private detective Carruthers, Ving Rhames, is assigned to the case.
Before Marcus returns to his duties, he attends Emma’s funeral, tries to console his suicidal wife, and sinks into a brief depression. A demonic and vengeful Caroline continues to kill left and right, and Carruthers interviews Elizabeth’s mother, learning that Elizabeth was a nice girl who had become abusive after dying briefly. Amidst the investigation, it’s revealed Caroline was a schoolteacher who nearly died from a seizure; Carruthers also interrogates Ray, a man connected to his murdered son and who was paid to kill Elizabeth.
Caroline pursues a hooker, Josie, to kill her in an apartment building, but Josie fights back. For trying to help Josie, Caroline petrifies Ray into falling down the stairs and sends his girlfriend Petra over the railing to hang. However, Josie manages to kill Caroline, releasing the possessing spirit. As Marcus begins to grow close to his best friend and coworker, Jenny, and his wife Carla spots them kissing, she uses a TV to electrocute herself in the bathtub. Paramedics arrive and attempt to revive her; Marcus performs CPR to bring her back to consciousness. Accompanying her to the hospital, Marcus covers up her suicidal act to prevent her from being taken to a psychiatric hospital.
At the apartment building crime scene, a terrified Josie informs the detectives that Caroline showed superhuman qualities. Carruthers arrives and pledges to help Josie; Marcus begins to realize Carla is behaving strangely, and that Emma and Carla are now possessed by an ancient spirit. Out of spite, Carla abducts Jenny and on her way home, kills Josie by running her over with her car.
Carruthers arrives at Carla’s house to warn Marcus about the evil spirit, which is Lilith, Adam’s first wife who hunts vengeance across the living. Leading the rest of the spirits that “hop” into bodies, she seeks vengeance against Adam, Eve and their children. Shortly after, Carla kills and beheads Carruthers with a sword. Marcus returns home and finds Carruthers’ head in a pot. Carla attacks him and injects him with a drug. Outside, Carla pushes Jenny, who is tied to a chair, into the pool. Marcus shoots Carla, who dies, and he attempts to save Jenny, but faints in the pool due to the drug. Paramedics arrive to rescue Marcus and Jenny, who both survive. After they leave the hospital, Jenny is now possessed by the spirit and she and Marcus part ways.
