Chris MacNeil (ELLEN BURSTYN) is an actress living in the Georgetown area of Washington, D.C. with her 12-year-old daughter, Regan (LINDA BLAIR). Working on her latest film with director Burke Dennings (JACK MacGOWRAN), Chris seems content with her life. That isn't true for Father Damien Karras (JASON MILLER), a psychiatric counselor for the Catholic Church who's also working in Georgetown. Beyond feeling that he's possibly lost his faith, he worries about his elderly mother who's sick, lives by herself in another city and doesn't have the money to better either condition.
After some strange events occur in the MacNeil's home related to Regan, Chris has the medical community give her the once over. Although they don't find anything wrong with her, Regan's attitude and behavior continue to worsen, with her language coarsening and her body doing odd physical feats. Chris begins to worry that something might seriously be wrong with Regan, and the sudden, seemingly suspicious death of Burke outside their home doesn't help her emotional state.
Having failed to come up with any physical or psychological malady regarding Regan's complete transformation into a now evil being, the doctors eventually suggest that Chris look into exorcism. Although she doesn't believe in that sort of thing, she contacts Father Karras who similarly doesn't believe in the archaic religious ritual that, as far as he knows, hasn't been conducted in several centuries.
Nonetheless, Karras meets with Regan and soon begins to suspect that she may indeed by possessed, and not by just any demon, but the Devil himself. After collecting enough information for the Church, Karras teams up with Father Merrin (MAX VON SYDOW), an elderly priest who's reportedly performed exorcisms - albeit secretly - in the past. As local police detective Lt. Kinderman (LEE J. COBB) investigates Burke's death, the two priests confront the seemingly possessed girl, hoping to save her from the entity that's possessed her body.