Valderrama is best known for the role of Fez in the sitcom That '70s Show and as Carlos Madrigal in From Dusk till Dawn: The Series. He was also the host of the MTV series Yo Momma, the voice of Manny in the children's show Handy Manny, and has had recurring roles on Grey's Anatomy as well as The Ranch. He is currently part of the main cast of NCIS, portraying Special Agent Nick Torres.

Valderrama has further performed in several prominent feature films, including Party Monster, Beauty Shop, Fast Food Nation, Unaccompanied Minors (2006), Larry Crowne, and The Adderall Diaries. He voiced the character of Prince Philippe Charming in the family animated film Charming.