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Paulson has appeared on Broadway in the plays The Glass Menagerie in 2005 and Collected Stories in 2010. She also starred in a number of independent films and had a leading role in the ABC comedy series Cupid (2009). She later starred in the independent drama film Martha Marcy May Marlene (2011) and received Primetime Emmy Award and Golden Globe Award nominations for her portrayal of Nicolle Wallace in the HBO film Game Change (2012). She was featured as Mary Epps in the 2013 historical drama film 12 Years a Slave, as Abby Gerhard in the 2015 romantic drama film Carol, and as Toni Bradlee in the 2017 political drama film The Post, all of which were nominated for multiple Academy Awards. Her other films include Serenity (2005), New Year's Eve (2011), Mud (2012), Blue Jay (2016), Ocean's 8 (2018), Bird Box (2018), Glass (2019), and Run (2020).

In 2011, Paulson began starring in the FX anthology series American Horror Story, playing different characters in many of the show's 10 seasons. For her performances in the series, she received five Primetime Emmy Award nominations and won two Critics' Choice Television Awards. In 2016, she portrayed real-life prosecutor Marcia Clark in the first season of the anthology series American Crime Story, subtitled The People v. O. J. Simpson, for which she garnered critical acclaim and numerous accolades, including the Primetime Emmy Award and the Golden Globe Award. In 2020, Paulson appeared in the FX limited series Mrs. America, and began starring as Nurse Mildred Ratched in the Netflix psychological thriller series Ratched. In 2021, she returned to American Crime Story to portray Linda Tripp in the third season of the show, subtitled Impeachment.