Peck's eldest son, Jonathan, was found dead in his home on June 26, 1975, in what authorities believed was a suicide. One of the reasons Peck accepted the role is that his agent thought it would help to distract him from the loss.

Harvey Stephens was largely chosen for this role based on the way he attacked Richard Donner during auditions. Donner asked all the little boys to "come at him" as if they were attacking Katherine Thorn during the church wedding scene. Stephens screamed and clawed at Donner's face and kicked him in the groin. Donner whipped the kid off him, ordered his blond hair dyed black, and cast him as Damien.

On Larry King Live, Dick Van Dyke revealed that he turned down the lead role in The Omen, which eventually went to Gregory Peck. Charlton Heston, William holden, and Roy Scheider also passed on the role.