Beginning in February 2016, Paulson starred in the first season of the true crime anthology series American Crime Story, subtitled The People v. O.J. Simpson, portraying prosecutor Marcia Clark. She garnered widespread critical acclaim for her performance and won various awards, including the TCA Award for Individual Achievement in Drama, the Primetime Emmy Award for Outstanding Lead Actress in a Limited Series or Movie, and the Golden Globe Award for Best Actress – Miniseries or Television Film.
In June 2016, the Human Rights Campaign released a video in tribute to the victims of the Orlando nightclub shooting; in the video, Paulson and others told the stories of the people killed there. In the fall of 2016, she starred in the sixth iteration of American Horror Story, subtitled Roanoke; in it, she was cast in the dual roles of British actress Audrey Tindall and tortured wife and yoga instructor Shelby Miller, the latter of whom is portrayed by Tindall's character in My Roanoke Nightmare, a documentary within the series. She also reprised her role of Lana Winters in the final episode of Roanoke, in which the character makes a crossover appearance.