Harris directed Tatyana Yassukovich in an unfinished feature length film for Duke University's Freewater Films named Darkmoor in 1983.
His first film appearance was in The Rachel Papers in 1989. He also played the role of the aged Will Robinson in the movie adaptation of the television series Lost in Space. More recently he played Dr. Charles Ashford in Resident Evil: Apocalypse, Benmont Tench in Jim Jarmusch's Dead Man, and Kenneth Branagh's character's doppelgänger in How to Kill Your Neighbor's Dog. Another notable role included King Henry VIII of England opposite Jodhi May and Natascha McElhone in the first adaptation of the novel The Other Boleyn Girl. He also portrayed Andy Warhol in I Shot Andy Warhol, and John Lennon in the television movie Two of Us. In 2005 he played the gruff Captain Anderson in the BBC2 adaptation of To the Ends of the Earth. He also played the role of Mac McGrath in the movie Mr. Deeds. He also plays the role of Eamon Quinn on FX'x hit series The Riches.
Harris' brothers Damian and Jamie also work in the entertainment industry.