A young married couple, Guy and Rosemary Woodhouse, move into an old, reputedly haunted New York City apartment building, the Bramford. Rosemary is a sweet and naive midwesterner, while Guy is an ambitious but struggling actor. They are looking to start a family and are enticed by the charm of the building, despite a friend's warnings about its dark history. After they settle in, they are quickly befriended by their eccentric and overly attentive elderly neighbors, Roman and Minnie Castevet, who take an unusual interest in the couple's lives.

As Guy's acting career begins to flourish, Rosemary's dream of becoming a mother comes true when she discovers she is pregnant. However, her joy is marred by a series of strange experiences and unsettling pain. She becomes increasingly isolated, the influence of her neighbors over her life grows, and she begins to suspect that there is more to their kindness than meets the eye. Overwhelmed by paranoia and ill health, Rosemary becomes distrustful of those closest to her, including Guy, and she fears that something sinister is being planned for her unborn child. She finds herself entangled in a web of deceit and ancient mysteries as she attempts to uncover the truth about the ominous forces surrounding her.