The film follows the trial of Father Richard Moore (played by Tom Wilkinson), a Catholic priest charged with negligent homicide after performing an exorcism on a young college student, Emily Rose (Jennifer Carpenter), who dies shortly after.

Erin Bruner (Laura Linney), a skeptical agnostic defense attorney, takes on Father Moore's case. As the trial progresses, chilling flashbacks reveal Emily's terrifying experiences—convulsions, hallucinations, speaking in tongues, and encounters with demonic forces.

While the prosecution argues Emily suffered from epilepsy and psychosis, Father Moore insists she was possessed by multiple demons and that medical science failed her. The film raises the central question: was Emily's death the result of a medical condition or a genuine case of demonic possession?