The Harmon family moves from Boston to Los Angeles to recover from mother Vivien's (Connie Britton) stillbirth and father Ben's (Dylan McDermott) infidelity with one of his students. Daughter Violet (Taissa Farmiga) starts at a new school, only to be terrorized by a group of girls. The family deals with intrusive neighbors Constance (Jessica Lange) and her daughter, Addie (Jamie Brewer), who has Down syndrome, along with Larry (Denis O'Hare), a previous homeowner who set fire to his entire family and, as a result, became scarred himself. Ben, a psychiatrist, sees patients out of his home, one of them, a possibly psychotic boy named Tate (Evan Peters), who becomes friends with Violet. Vivien rehires the house's former housekeeper, an elderly Moira (Frances Conroy), who appears to Ben as a young, seductive maid (Alexandra Breckenridge). Ben and Vivien eventually have sex, once after a fight, and later while she thinks he has dressed up in a bondage suit. She later tells Ben she's pregnant.

American Horror Story's first season follows the Harmon family: Ben (Dylan McDermott), Vivien (Connie Britton) and Violet (Taissa Farmiga), who move from Boston to Los Angeles after Vivien gives birth to a stillborn baby and Ben has an affair with Hayden (Kate Mara), one of his students. On arrival, they learn from Marcy (Christine Estabrook), the real estate agent, that the previous owners of their new mansion, a gay couple (Zachary Quinto and Teddy Sears), apparently died in a murder/suicide. Their neighbor Constance (Jessica Lange) and her daughter Addie (Jamie Brewer) become frequent, if sometimes unwelcome, guests. Addie, who has Down syndrome, seems to have a supernatural connection with the house's mysterious past. Larry Harvey (Denis O'Hare) also harasses Ben and murders Hayden, when Hayden arrives to try and resume her affair with Ben. The house also "comes with" Moira O'Hara (Frances Conroy/Alexandra Breckenridge), a housekeeper who, to men, appears as young and seductive, but, to women, old and matronly.

Ben begins seeing patients out of his home office. One in particular, the possibly psychotic Tate Langdon (Evan Peters), takes a keen interest in kindred spirit Violet, who suffers from depression. Ben is unaware that Tate is both a ghost and the son of Constance. As the family settles into the home, bizarre and often violent events begin to occur with increasing regularity. It is soon revealed that there have been upwards of 20 violent deaths in the home over the course of its history, so much so that it is known on sightseeing tours as "The Murder House". The family struggles with their own personal tribulations, oblivious to the reality of their home even as more people die and take up residence as ghosts. Upon exploring the attic, Vivien discovers a bondage suit. Unknowingly, she is raped by Tate whom she mistakes for Ben in the bondage suit. Vivien's rape results in the rare occurrence of becoming pregnant with twins by different fathers. It is later revealed that Tate's motive in the rape was to sire a baby for Nora (Lily Rabe), a ghost in house who lost her own child. Several ghosts in the house, including Hayden and Nora, conspire to drive Vivien mad so that they can raise the babies as their own.

On Halloween, the one day in which the dead can walk the earth among the living, Violet learns that Tate is an infamous school shooter, who killed a library full of his fellow teenagers (as well as crippling a teacher and setting Larry Harvey on fire) as a ploy to punish his mother Constance for having Tate's younger (and deformed) brother euthanized. Addie is run over by a car, leading to Constance failing to get her corpse moved to the house property to imprison her spirit so that she can be reunited with her brother's ghost. Vivien meanwhile learns from the "Murder House Tour", that the house was the home of a back alley abortionist and that the monstrous ghost in the basement of the house is the ghost of the doctor's son, who was killed by a patient's vengeful boyfriend and resurrected as a monstrous "Infantata" monster.

Faced with the monster Tate is, and her own romantic feelings for him, Violet kills herself, something she doesn't realize was successful until weeks later when she realizes she cannot leave the house. Tate convinces Violet to lie and help her father commit Vivien to an insane asylum, as Ben is convinced that the second father of her child is Luke (Morris Chestnut), a neighborhood security officer. Meanwhile, Constance enlists the help of a medium (Sarah Paulson) to help her talk to Addie. Constance discovers from the medium, to her horror, that Tate's child with Vivien will become the Anti-Christ. When Moira and Violet tells Ben the truth about her being a ghost, Tate being the "rubber man", and the evil in the house, he has Vivien freed from the asylum. Violet breaks up with Tate after Chad (Quinto), one of the members of the gay couple, reveals that Tate raped Violet's mother and murdered him and his boyfriend.

Vivien gives birth to the twins in the house, with Moira recruiting the more benevolent ghosts of the house to help deliver the children. Sadly, Vivien and one of the newborn babies die, leaving Ben with the sole surviving twin. Ben then tries to get into contact with his now dead wife and daughter, who refuse to show themselves. As he grieves he contemplates suicide to be with them. Instead Vivien shows herself and convinces Ben to leave the house immediately for the protection of the baby. As Ben is leaving the house he is caught and murdered by Hayden, who hangs him to simulate a suicide. Hayden attempts to take the baby, but Constance, helped by the ghost of a lover named Travis (Michael Graziadei), whom Hayden murdered for revenge against Constance, takes the child instead. Constance hides the baby and tells the police that Ben killed himself out of grief for his wife's death and that Violet (whose body is never found) ran off with the surviving child.

Now trapped in the house, the Harmons (Vivien, Ben, Violet, and the deceased twin) team up with Moira to keep further families from the house by scaring new residents into leaving. Tate meanwhile has consigned himself to living with Hayden, both of which have been blocked out by the Harmons using a trick that Tate taught Violet when she first died. Elsewhere, Constance (who left town to create a cover story regarding the Harmon child she is now raising) returns to Los Angeles but finds that her grandson (The Anti-Christ) has murdered his nanny, after returning home from getting her hair done. She slowly walks to the young smiling, giggling boy. She then smiles and touches his hair and whispers "Now what am I gonna do with you?"