American diplomat Robert Thorn and his wife Kathy are living in Rome, where Kathy gives birth to a boy who Robert is told died immediately. Hospital chaplain Father Spiletto persuades Robert to secretly adopt another baby whose mother just died in childbirth. Robert does not tell Kathy the child is not their own. They name him Damien.




Five years later, Robert is Ambassador to the United Kingdom in London when mysterious events begin to plague the Thorns: a menacing Rottweiler appears at their home, Damien's nanny publicly hangs herself during his fifth birthday party, new nanny Mrs. Baylock arrives unannounced, Damien violently resists entering a church, and Damien's presence terrifies animals at a safari park. Father Brennan warns Robert about Damien's origins, hinting that he is not human and insisting Robert take Communion. He tells Robert that Damien is the son of Satan, that Kathy is pregnant, and that Damien will kill his unborn sibling and parents. Later, Father Brennan is killed by a falling lightning rod. Kathy tells Robert she wants an abortion, which he opposes. Damien knocks Kathy over a railing to the floor below, injuring and causing her to miscarry.




Photographer Keith Jennings notices shadows in photographs of the nanny and Father Brennan that presaged their deaths. Keith shows Robert the photos along with news clippings and Biblical passages that suggest the coming of the Antichrist. He accompanies Robert to Rome to investigate Damien's birth. They learn that a fire destroyed the hospital, including Kathy's maternity records, and killed the staff on duty. They find Father Spiletto in a monastery severely burned, mute, blind in one eye, and partially paralyzed. He directs them to the cemetery where Damien's biological mother is buried. In Damien's mother's grave, Robert and Keith find a jackal carcass and, in the next plot, a child's skeleton with a shattered skull. Robert realizes that the child was his own son, murdered so that Damien could take his place. A pack of Rottweilers drives Robert and Keith from the cemetery.




Robert calls Kathy in hospital to tell her she must leave London. Before she can do so, Mrs. Baylock throws her to her death from a window. Robert and Keith meet Antichrist expert Carl Bugenhagen in Israel who says if Damien is the true Antichrist, he will bear a birthmark in the shape of three sixes. Carl gives Robert seven daggers with which to kill Damien on hallowed ground. Robert refuses to do so, but Keith remains convinced about the necessity of it. Afterwards, Keith is decapitated by a sheet of glass. Robert then reluctantly accepts his task.




Robert finds the birthmark on the sleeping Damien's scalp and is attacked by Mrs. Baylock, whom he stabs to death. Armed with the daggers, Robert drives Damien to a cathedral. His erratic driving draws the attention of the police. Robert drags a screaming Damien onto the altar to kill him, but is shot to death by police before he can do so.




The double funeral of Kathy and Robert is attended by the U.S. President and the First Lady, who have Damien with them. Damien turns and smiles at the camera.