Duplass starred in the Amazon Video comedy-drama series Transparent (2014–2019), and co-created the HBO comedy-drama series Togetherness (2015–16) and the HBO anthology series Room 104 (2017–2020).
Duplass was born in New Orleans, Louisiana, the son of Cynthia (née Ernst) and Lawrence Duplass. He was raised in a Catholic family, and attended Jesuit High School. Duplass graduated from the University of Texas at Austin with an MFA in film. His ancestry includes French Cajun, Italian, Ashkenazi Jewish, and German.

Duplass attributes much of his and his brother's love for film to his appreciation for Raising Arizona. In an interview with Robert K. Elder for The Film That Changed My Life, Duplass speculates on what might have happened had he not seen the film in his youth.

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