Rome, Italy, June 6, 1966, 6:00 am. Robert Thorn (Gregory Peck) is an American diplomat who hurries to a local hospital where his pregnant wife (Lee Remick) is going into labor. When he gets to the hospital, he is informed that his child was a stillbirth. A priest named Father Spiletto (Martin Benson) then offers him the choice to adopt a baby boy just born at the same time who has no parents. Thorn is reluctant to do so but knowing his wife will be devestated by the news of the death of her real child he agrees to the adoption.
The boy is called Damien and moves to England with his mother and father when his father is appointed US ambassador to England. When Damien (Harvey Stephens) is celebrating his fifth birthday party, the family's nanny hangs herself in front of everyone and at the same time, the house is being watched by a rottweiler dog. In the background, a news photographer named Keith Jennings (David Warner) is present taking pictures.
A few days later, a new nanny, named Mrs. Baylock (Billie Whitelaw) is sent to replace her but it is clear that she is not as she seems.
Mrs. Baylock immediately challenges Kathy Thorn's authority when she is instructed to dress and ready Damien to attend a church wedding with them, but she does as she is told. As Thorn leaves the house, he is badgered by Jennings about circumstances around the previous nanny's death.
The Thorns travel to the church one Sunday and Damien becomes more fearful as their car approaches the church. He has a violent reaction in which he injures his mother trying to get away. The car pulls away hurridly and while the Thorns discuss Damien's reaction and whether he should be examined by a doctor, they realize he has never been sick a day in his life.
Later, in his office, Thorn is visited by a priest, named Father Brennan (Patrick Troughton), who claims to have been present during Damien's birth in Rome five years ago. He begs Thorn to accept Christ, because only then can he fight the son of the devil. The priest is escorted out by security and Jennings takes note of the visitor, snapping pictures. While developing the pictures of the day, Jennings notices the priest has a dark object like a javelin over his head in the pictures he appears in, but the anomaly doesn't appear anywhere else on the film.
The next scene shows Kathy Thorn with Damien, traveling through a safari park, and various animals react with fear or anger towards Damien. It climaxes in a harrowing scene where a group of baboons attack the car that Kathy is driving forcing her to speed away.
Meanwhile, Robert Thorn is followed by the priest that met with him earlier and is pulled aside at a public event; the priest tells him that his wife is in danger and he needs to talk to him. Jennings is also at the event, taking pictures. The pictures again show the dark anomaly above the priest.
The next day, when Thorn meets with the priest again, Father Brennan again tells him that Damien is the son of the devil, born of a jackal, and will kill everyone around him and will kill his wife's unborn child as well as his wife. The priest instructs Thorn to go to Israel to the city of Megiddo to find a man who can tell him how to kill the son of the devil. Brennan tells Thron about an ancient prophecy that an antrichrist will be born, grow to manhood, and take over the world and lead it into death and destruction. Thorn thinks he is crazy and says never to bother him again. As the priest leaves the park, a sudden rainstorm comes up and the priest is impaled by a church spire in a freak accident while trying to get into a nearby church.
Thorn goes home and his wife tells him she is pregnant. Startled by this news, he also receives a phone call telling him to examine the newspaper's cover story about the priest's bizarre death. Kathy has been agitated by Damien of late, causing her to visit a therapist, and tells Robert she wants to terminate the pregnancy. Disturbed by this, Thorn decides to go to the therapist to discuss Kathy's concerns. While Thorn is out, Damien's mother falls over a bannister after being knocked over by Damien, injuring her and thusly killing her unborn child.
Jennings calls for Robert Thorn to meet him and he shows him the photographic anomalies with the old nanny and Father Brennan. Thorn tells him about the priest's warnings. Jennings said he is now involved because he found an anomaly on a picture of himself in which he has no neck. Jennings takes Thorn to the priest's residence, which he has access to due to the police investigation into his death, and they find an odd collection of crosses and Bible pages everywhere.
Thorn and Jennings travel to Italy together to find the priest that gave him Damien at the hospital. They quickly learn that the hospital where Damien was born burned down in a mysterious fire five years ago, along with all the birth records. They go and find the priest, Father Spiletto, living in a remote monestery only to find him in very grave health. He is severly burned and has movement only in his left hand. Using a piece of charcoal, the priest points him in the direction of Damien's true mother.
Thorn and Jennings travel to a local cemetery that lies in ruins, the former site of a shrine dedicated to the devil-god Techulca. They find the gravesites of both Damien's mother and the Thorns' baby... the mother's grave contains a jackal's remains, and the other grave contains a baby whose skull was crushed. Thorn realizes his baby was murdered (apparently by Spiletto and the Satanic conspirators) in order to swap its place with Damien. As they leave the cemetery, they are attacked by a pack of dogs led by a black rottweiler, and manage to escape.
Robert calls his wife who is in hospital and tells her to come to Italy. However, she is thrown out of the hospital window by Mrs. Baylock as she gets up out of her bed.
Back at the hotel, Thorn receives a phone call and finds out his wife has apparently jumped to her death from her hospital room. In his grief, he tells Jennings that he wants to go to Megiddo and that he wants Damien to die.
Thorn and Jennings travel to Jerusalem and find that Megiddo is an archaelogic dig, almost completely underground. A man appears and takes them to Carl Bugenhagen (Leo McKern), the man the priest told Thorn to find. Bugenhagen is an elderly English archeologist who tells Thorn that he has been expecting him. He insists on talking to Thorn alone as Jennings is forced to wait outside the dig site. Bugenhagen gives Thorn seven special daggers, explains their significance and how to kill Damien. He also tells Thorn that Damien will have the mark of the Beast, three sixes, somewhere on his body.
Thorn and Jennings leave, and Thorn flings the bundle of knives away saying he won't kill a child. Jennings goes after the knives, saying he will do it, and is suddenly killed in a freak accident when a truck mysteriously shifts into reverse by itself and a sheet of glass slides off the truck and decapitates Jennings in front of Thorn.
Thorn flies home alone... with the knives, determined to kill Damien. When he returns to his house that night, he finds a rottweiler dog waiting for him, he succeeds in trapping it in the basement. Thorn then takes some scissors and searches the sleeping Damien's scalp for a birthmark in the form of a series of three sixes. Upon doing so, he discovers the sixes and all doubt about Damien's true identity are diminished. Mrs. Baylock then attacks him and as he takes Damien down the stairs. He fights her briefly before stabbing her with a kitchen knife. He then drags Damien into his car and speeds off to the local church.
A police officer sees him speeding and pursues him. Thorn drives to the church with several police cars on his tail. He goes into the church and takes Damien kicking and screaming to the alter. He is about to stab him with the daggers, but he is shot by a police officer.
The film ends with Robert Thorn and his wife's funeral in Arlington National Cemetery. Damien is seen having has been adopted by Robert's brother... who is the president of the United States. Damien looks into the camera and smiles somewhat menacingly as the prophecy of the antichrist is being fullfilled....