Clark Duke was born in Glenwood, Arkansas. His parents are Angela and Ronnie Duke. Along with best friend Michael Cera, Duke created, wrote, directed, and produced the web series Clark and Michael (2007) in which he plays a fictional version of himself. The pilot episode was directed by Duke as his college thesis film at Loyola Marymount University.

He is a regular on the television series Greek (2007) as Rusty's Christian dorm roommate, Dale. Duke once auditioned for the role of Fogell in the film Superbad (2007), but despite being declined the role, due to his friendship with Cera he was on set quite a bit and was ultimately given the small role of 'Party Teenager #1'.