He started his career at the Steppenwolf Theatre before making his Broadway debut as a playwright for August: Osage County (2007), for which he received the Pulitzer Prize for Drama and the Tony Award for Best Play.

His works include Killer Joe, Bug, Man from Nebraska, August: Osage County, Superior Donuts, Linda Vista, and The Minutes.

In film and television, he is known for his portrayal of Andrew Lockhart in seasons 3 and 4 of Showtime's Homeland, and pyramid-scheme con-artist Nick on the HBO comedy Divorce.

In 2017, Letts starred in three critically acclaimed films: Azazel Jacobs' The Lovers, Greta Gerwig's Lady Bird, and Steven Spielberg's The Post.

Lady Bird earned Letts a nomination for the Screen Actors Guild Award for Outstanding Performance by a Cast in a Motion Picture.

He appeared in Jerry Flemmons' O Dammit!, which was part of a new playwrights' series sponsored by Southern Methodist University.

Two years later, the play premiered at the Next Lab Theater in Evanston, Illinois, followed by the 29th Street Rep in New York City.

In 2012, Letts gained attention for his Broadway debut performance in the revival of Edward Albee's Who's Afraid of Virginia Woolf?

[citation needed] His most famous, August: Osage County, premiered at the Steppenwolf Theatre in Chicago on June 28, 2007.

Letts has also been a finalist for the Pulitzer drama prize for his plays Man from Nebraska and The Minutes; the Pulitzer committee described The Minutes as a "shocking drama set in a seemingly mundane city council meeting that acidly articulates a uniquely American toxicity that feels both historic and contemporary.

[14] In 2018, Letts was cast in the second season of USA Network's anthology crime drama series The Sinner, opposite Bill Pullman and Carrie Coon.

He also wrote the screenplay for the 2021 Netflix feature film The Woman in the Window, starring Amy Adams, based on the eponymous psychological thriller by A.J.