Raised in the Bronx, Desmond Harrington went to a Catholic prep school and worked as a bartender and construction worker before beginning his acting career. His film debut was in Luc Besson's The Messenger: The Story of Joan of Arc, which led to a visit to the Sundance Film Festival and a few small roles in independent features such as Drop Back Ten and Massholes. In 2001, Harrington appeared in two big projects, Christine Lahti's directorial debut, My First Mister, and Riding in Cars With Boys with Drew Barrymore. He continued to work in dramas (We Were Soldiers), but then made the thriller Ghost Ship. He played a starring role in a short film called Life Makes Sense if You're Famous, and made his television debut in the miniseries Taken. In 2003, Harrington stuck with thrillers for a leading role in Wrong Turn.
Harrington found continued success on the small screen with recurring roles in Dragnet, Sons & Daughters, and most prominently the Showtime serial-killer series Dexter. Even with these steady gigs, he worked in projects like TiMER and Life Is Hot in Cracktown.