The story takes place in 1964 and follows the patients, doctors and nuns who occupy the Briarcliff Mental Institution, located in Massachusetts and founded to treat and house the criminally insane. The wardens who run the institution include the stern Sister Jude, her protégé Sister Mary Eunice and the founder of the institution, Monsignor Timothy Howard. The doctors charged with treating the patients at the asylum include psychiatrist Dr. Oliver Thredson, who is a psychiatrist assigned to evaluate Kit Walker, who believes his wife Alma was kidnapped by aliens. It is revealed that Thredson actually committed the murders, and got himself assigned to Walker’s case to make sure he could pin the murders and Alma's disappearance on him. Kit is duped into taping a confession and is arrested for the murders but later escapes custody. Thredson also tries to "reform" the patient Lana Winters, the lesbian journalist who attempts to expose Briarcliff’s for their mistreatments of patients. Winters is in a relationship Wendy, who was blackmailed by Sister Jude into committing Winters to stop her from exposing Briarcliff, which she is then later on murdered by Thredson. Thredson agrees to help Winters escape the asylum, but she finds out about his dark secret and that he sees her as the mother he never had. He keeps her prisoner and tries to turn her into his mother figure. He rapes her, and is later going to kill her for his "indiscretion". Winters later escapes, only to end up back at Briarcliff, but it is then she learns that she is pregnant with Thredson's baby.
The sadistic scientist Dr. Arthur Arden, which you later figure our that Arden is a former Nazi whose experiments have produced "Raspers", mutated former patients, who lurk in the woods surrounding the institution, and who are fed the flesh of dead patients.
The patients, many of whom claim to be unjustly institutionalised, include lesbian journalist Lana Winters, accused serial killer Kit Walker, nymphomaniac Shelley and alleged murderer Grace Bertrand. Briarcliff's inhabitants are routinely subject to supernatural and scientific influences, including demonic possession and extraterrestrial abduction. The season primarily takes place throughout the 1960s with flash-forwards to 2012.
Sister Jude was once a flirty nightclub singer who unintentionally killed a young girl in a drunk driving hit and run accident in 1949. This led her to become a nun and then work at Briarcliff. Sister Mary Eunice is a shy and innocent nun who fears Sister Jude. Later, she becomes possessed by the Devil during an exorcism of another patient and becomes cruel and evil. Sister Jude is terrorised by the memory and goes to see the family of the dead girl. When is when she learns the girl survived the accident with only a few broken bones. Sister Jude figures that God had a plan for her all along, and decides that it is her job to destroy all the remaining evil at Briarcliff. A possessed Sister Mary Eunice is able to get Sister Jude deposed and committed. Mary Eunice takes over Briarcliff, with Dr. Arden's help. She nurses the weakened Monsignor Howard back to health and he tries to perform a failed exorcism on her. But later Howard kills her by throwing her off the third floor balcony which also realised the demon inside her.
Meanwhile, believing his wife is dead or missing, Kit takes a fancy with inmate Grace Bertrand, who had murdered her family after her father sexually abused her. She and Kit got caught having sex in the kitchens before his arrest which they’re then separated with the idea of them to be sterilised. However, she is abducted by the same aliens that had taken Alma but is later returned back to Briarcliff, heavily pregnant and about to give birth. He negotiates with Monsignor and arranges for Grace, himself, and their baby to be released. However when they arrive at his old home to find his wife Alma and with her own baby.
Lana captures a confession from Dr. Thredson admitting to his crimes, but corners him in his house to say she has turned the tape over to the police and hopes he rots in jail. He states, because he is insane, no jury will convict him, grasping for a gun in a drawer she shoots him in the head. In the present, she has become a famous television reporter and gets Briarcliff closed down for its treatments. Lana reveals that Monsignor Howard committed suicide after she threatened to expose his neglect of the patients. She also goes on to say that Kit took in Sister Jude, after Alma was committed to Briarcliff for killing Grace. Jude's dementia worsens and she is taken into the woods by the children. Her mind is healed for a while but she later grows frail and dies. Kit is later abducted by the same aliens that took Grace and Alma after he is diagnosed with pancreatic cancer.
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