Brown portrayed Christopher Darden in the FXlimited series The People v. O. J. Simpson: American Crime Story (2016), which earned the Primetime Emmy Award for Outstanding Supporting Actor in a Limited Series or Movie. For his role as Randall Pearson in the NBC drama series This Is Us (2016–2022), he earned the Primetime Emmy Award for Outstanding Lead Actor in a Drama Series. He was further Emmy-nominated for his comedic roles in the Fox Brooklyn Nine-Nine (2018) and the Amazon Prime comedy series The Marvelous Mrs. Maisel (2019).
For his role in American Fiction (2023), he was nominated for the Academy Award for Best Supporting Actor. Brown is also known for his leading roles in films such as Hotel Artemis (2019), Honk for Jesus. Save Your Soul. (2022), and Biosphere (2023) as well as supporting roles in Marshall (2017), Black Panther (2018), and Waves (2019). He has voiced roles in the 2019 animated films The Angry Birds Movie 2 and Frozen II.
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