The book centers on Rosemary Woodhouse, a young woman who has just moved into the Bramford, an old Gothic Revival style New York City apartment building with her husband, Guy, a struggling actor. The pair is warned that the Bramford has a disturbing history involving witchcraft and murder, but they choose to overlook this. Rosemary has wanted children for some time, but Guy wants to wait until he is more established.
Rosemary and Guy are quickly welcomed to Bramford by neighbors Minnie and Roman Castevet, an eccentric elderly couple. Rosemary finds them meddlesome and absurd, but Guy begins paying them frequent visits.
After a theatrical rival suddenly goes blind, Guy is given an important part in a stage play. Immediately afterward, Guy unexpectedly agrees with Rosemary that it is time to conceive their first child.
Guy's performance in the stage play brings him favorable notice and he is subsequently cast in other, increasingly important roles; he begins to talk about a career in Hollywood.
After receiving a warning from a friend, who also becomes mysteriously ill, Rosemary discovers that her neighbors are the leaders of a Satanic coven, and she suspects they intend to steal her child and use it as a sacrifice to the Devil. Despite her growing conviction, she is unable to convince anyone else and soon becomes certain that there is no one actually on her side, least of all her own husband. Ultimately, Rosemary finds that she is wrong about the coven's reason for wanting the baby — the baby is the Antichrist and Guy is not actually the father.