When I was twenty-two it was a lot harder to get hurt by women. It was easier for me to, you know, cheat on a girlfriend. I can't lie like that anymore.

That year he starred in The Simpsons episode "Midnight Towboy". Dillon did voiceover work in the 1987 documentary film Dear America: Letters Home from Vietnam. He made his Broadway debut with the play The Boys of Winter in 1985.

In 1990 he won the Independent Spirit Award for Best Male Lead for Drugstore Cowboy and in 2006 won the Independent Spirit Award for Best Supporting Male for Crash and the San Sebastián International Film Festival Donostia Lifetime Archievement Award. He began acting in the late 1970s gaining fame as a teenage idol during the 1980s appearing in films such as Little Darlings (1980) My Bodyguard (1980) Tex (1982) Rumble Fish (1983) The Outsiders (1983) Drugstore Cowboy (1989) Singles (1992) Beautiful Girls (1996) There's Something About Mary (1998) Wild Things (1998) Herbie: Fully Loaded (2005) Crash (2005)You Me and Dupree (2006) and Armored (2009).