Lankester Merrin is a veteran Catholic priest who is on an archaeological dig in Iraq. There he finds an amulet that resembles the statue of Pazuzu, a demon whom Merrin had defeated years before. Merrin then realizes the demon has returned to seek revenge.
Meanwhile, in Georgetown, actress Chris MacNeil is living on location with her pre-teen daughter Regan, where Chris has just wrapped the final scene of a film about student activism directed by her friend and associate Burke Dennings. After playing with a Ouija board and contacting a supposedly imaginary friend named Captain Howdy, Regan begins acting strangely, including making mysterious noises, stealing, constantly using obscene language, and exhibiting abnormal strength. Chris hosts a party, only for Regan to come downstairs unannounced, telling one of the guests, who is an astronaut, "You're gonna die up there", and then urinating on the floor. Regan also causes her bed to shake violently, much to her and the mother's horror. Chris consults physicians, but Dr. Klein and his associates find nothing medically wrong with her daughter, despite Regan undergoing a battery of diagnostic tests.
One night when Chris is out, Burke Dennings is babysitting Regan, only for Chris to come home to hear he has died falling out the window. Although this is assumed to have been an accident, given Burke's history of heavy drinking, his death is investigated by Lieutenant William Kinderman, who interviews Chris, as well as priest and psychiatrist Father Damien Karras, who has lost faith in God after his frail mother died.
After the doctors decide that an exorcism may be the only way to help Regan, Chris arranges a meeting with Karras. After recording Regan speaking backwards and witnessing the etching of the words "Help Me" on her stomach, Karras is convinced Regan is possessed. Believing her soul is in danger, he decides to perform an exorcism. The experienced Merrin is selected to do so instead, with Karras present to assist.
Both priests witness Regan perform a series of bizarre, vulgar acts, and confine her to her bedroom. They attempt to exorcise the demon, but a stubborn Pazuzu toys with them, especially Karras. Karras shows weakness, and is dismissed by Merrin, who attempts the exorcism alone. Karras enters the room and discovers Merrin has died of a heart attack. After failing to revive Merrin, Karras confronts the mocking, laughing spirit of Pazuzu, tackling the demon to the ground. At Karras's plea, Pazuzu then possesses Karras, leaving Regan's body. In a moment of self-sacrifice, the priest throws himself out of the window before Pazuzu can compel him to harm Regan, and is mortally injured. By chance, Father Dyer, an old friend of Karras, happens upon the scene and administers the last rites to his friend.
A few days later Regan, who is now back to her normal self, prepares to leave for Los Angeles with her mother. Although Regan has no recollection of her possession, she gives Father Dyer a kiss, a likely hint at posthumous thanks to Father Merrin and Father Karras. Kinderman, who narrowly misses their departure, befriends Father Dyer as he investigates Karras' death.
Who told the astronaut that he was going to die?
Regan