Henry was born in Fayetteville, North Carolina and raised partly in Washington, D.C. His father was in the military, and his mother, Willow Dean Kearse, was an educator.

In 2011, he received further success in his Broadway debut as a part of the original cast of the musical The Book of Mormon opposite Josh Gad and Andrew Rannells.

In 2013, he had a brief but recurring role as Winston Scrapper in HBO's Boardwalk Empire appearing in the episodes "Havre de Grace" and "Farewell Daddy Blues".

In 2016, Henry received critical acclaim and recognition for his starring role as Alfred "Paper Boi" Miles in the FX comedy-drama series Atlanta.

In 2018, he returned to Broadway in the revival of Kenneth Lonergan's Lobby Hero opposite Chris Evans, Bel Powley, and Michael Cera.

He appeared in Steve McQueen's acclaimed heist film Widows portraying Jamal Manning, a crime boss and politician in the Chicago.

Alissa Wilkinson of Vox declared "Brian Tyree Henry continues his run as the actor to watch, thanks to his appearance here as a charismatic and menacing political candidate.

In 2021, he starred as Bernie Hayes in Godzilla vs. Kong alongside Millie Bobby Brown and as Phastos in the Marvel Studios film Eternals directed by Chloe Zhao.

In his final role of the year, Henry starred in Lila Neugebauer's A24 drama Causeway opposite Jennifer Lawrence as mechanic James Aucoin.

[14][15] In a review for The Independent, Adam White wrote: "Henry lends each hushed gap in James's tale the feel of a sledgehammer.