Lost Souls is a movie about a group of Catholics who go to a mental institution to perform an exorcism on the murderer George Viznik (Brad Greenquist). Father Lareaux (Sir John Hurt), Deacon John Townsend (Elias Koteas), Father Frank Page (Brian Reddy), and the teacher Maya Larkin (Winona Ryder) are part of the team.
During the exorcism, Father Lareaux falls into a coma and the group is unable to exorcise George Viznik. Maya, who was possessed and exorcised in the past, deciphers Viznik's coded writings and believes that the writer Peter Kelson (Ben Chaplin) may be the Antichrist to be incarnated by Satan.
Maya seeks out Peter, who has been raised by his atheist uncle Father James (Philip Baker Hall). Peter initially does not believe Maya's claims, but strange things start happening to him. As Peter and Maya investigate together, they discover the possibility of saving Peter's soul from being taken over by the Antichrist.