He is best known for creating and producing a number of television series including Popular (1999–2001), Nip/Tuck (2003–2010), Glee (2009–2015), American Horror Story (2011–present), Scream Queens (2015–2016), American Crime Story (2016–present), Pose (2018–2021), 9-1-1 (2018–present), The Politician (2019–2020), 9-1-1: Lone Star (2020–present), Ratched (2020), American Horror Stories (2021–present), and Dahmer – Monster: The Jeffrey Dahmer Story (2022). Murphy also directed the 2006 film adaptation of Augusten Burroughs' memoir Running with Scissors, the 2010 film adaptation of Elizabeth Gilbert's memoir Eat, Pray, Love, the 2014 film adaptation of Larry Kramer's play The Normal Heart, and the 2020 film adaptation of the musical The Prom.

Murphy has received six Primetime Emmy Awards from 36 nominations, a Tony Award from two nominations, and two Grammy Award nominations. He has often been cited as "the most powerful man" in modern television, including having signed the largest development deal in television history with Netflix. Murphy is noted for having created a shift in inclusive storytelling that "brought marginalised characters to the masses".