Harris began his career as a child actor. His first significant roles came in 1988, when he starred in two movies: the film Clara's Heart, a drama with Whoopi Goldberg that won him a Golden Globe nomination, and Purple People Eater, a children's fantasy. The following year he won the lead in Doogie Howser, M.D., for which he was again nominated for a Golden Globe. After Doogie Howser's four-season run ended in 1993, Harris played a number of guest roles on television series, before taking his first film role as an adult in 1995 in the little-seen shocker Animal Room. Since then his film work has included supporting roles in The Next Best Thing, Undercover Brother, Starship Troopers and Harold & Kumar Go to White Castle, in which he played a drug-crazed, lecherous parody of himself.

From 1999 to 2000, Harris starred with Tony Shalhoub in the sitcom Stark Raving Mad, which lasted twenty-two episodes. He has taken lead roles in a number of made-for-television features, includ