Starting at an archaeological dig in Al-hadar near Nineveh in Iraq, Father Lankester Merrin (Max von Sydow), an archaeologist, visits a site where a small stone is found, resembling a grimacing, bestial creature. Merrin travels onward to find the strange statue of Pazuzu, which has a head similar to the one found earlier. He also encounters two riflemen and two dogs fighting each other.
Meanwhile, another priest, Father Damien Karras (Jason Miller), a young priest at Georgetown University in Washington, D.C., begins to doubt his faith while dealing with his mother's terminal illness.
The main story follows Chris MacNeil (Ellen Burstyn), an actress filming in Georgetown, who notices dramatic and dangerous changes in the behavior of her 12-year-old daughter, Regan MacNeil (Linda Blair). Regan has a seizure, then exhibits strange, unnatural powers including levitation and great strength. Regan curses and blasphemes in a demonic male voice. Chris initially believes Regan's changes are related to puberty, but doctors suspect a lesion in her brain. Regan endures a series of unpleasant medical tests. When X-rays show nothing out of the ordinary, a doctor advises that Regan be taken to a psychiatrist, whom she assaults. Paranormal occurrences continue, including a violently shaking bed, strange noises, and unexplained movements. Along with these things, the director of Chris MacNeil's film, Burke Dennings (Jack MacGowran), is found brutally murdered outside the MacNeil residence after being asked to babysit Regan.
When all medical explanations are exhausted, a doctor recommends exorcism, suggesting that if Regan's symptoms are a psychosomatic result of a belief in demonic possession, then perhaps an exorcism would have the psychosomatic effect of ending them. In desperation, Chris consults Karras, since he is both a priest and a psychiatrist. During a period in which Karras observes Regan, Regan refers to herself as the Devil. Despite his doubts, Karras decides to request permission from the Church to conduct an exorcism.
Merrin, an experienced exorcist, is summoned to Washington to help. He and Father Karras try to drive the spirit from Regan.The demon threatens and taunts both priests, both physically and verbally (including the demon using the voice of Karras' mother), and Merrin dies of a heart attack. Karras attempts to perform CPR to no avail. Regan giggles as Karras tries to save Merrin. Karras strikes her and chokes her, challenging the demon to leave Regan and enter him. The demon does so, whereupon the priest throws himself through Regan's bedroom window and falls down the steps outside. At the bottom, a devastated Father Dyer (William O'Malley) - and friend of Father Karras - administers last rites as Father Karras dies. Regan is restored to health and does not appear to remember her ordeal. Chris and Regan leave Georgetown and their trauma behind.
