Thomas arrived in Hollywood in 1980, and was cast in an episode of CHiPs, which he never filmed, because next day he was set to co-star as Dave Christian, a member on the 1980 gold medal Olympic hockey team in Miracle on Ice, a mini-series. While at Ohio, the head of the theater department, Robert Winters, had sat Duffy down and told him he couldn’t be a hockey player and an actor. They both had a good laugh after MOI aired. Duffy made his feature film debut as Nirvana, Charles Bronson’s chief nemesis in Death Wish II. He went on to appear in such films as To Live and Die in L.A., The Abyss, Crossroads and State of Grace and guest starred on Night Court, The Fall Guy, The Twilight Zone, MacGyver, and recurred on A Year in the Life on television.

Duffy appeared in the 1992 film The Waterdance, an acclaimed but oft overlooked feature that won the 1992 Sundance Festival Audience award and the 1993 Independent Spirit Best Picture award, with good friend, William Forsythe.

His father, Peter T. Duffy, was killed by a drunk driver in his hometown of Woodbridge, New Jersey, in 1992. Thomas was filming The Mambo Kings at the time, and the producers cut a scene so he could return home. His youngest sister, Patricia, was also killed by a drunk driver in Woodbridge, in 1990.

Thomas was filming Wagons East! in 1994 with John Candy in Durango, Mexico, when John died from a heart attack.

In 1999, Duffy played Sam Moxon in Varsity Blues, a film about Texas high school football. Duffy was almost killed when his car was struck by a hit-and-run driver, while filming in Austin, Texas.

In 2010, Thomas plays the role of executive Whitman Hayes in the film The Candidate, to be released in 2011.

Thomas appears in the film Rubber, which opened in the US in 2011 from Magnet Releasing. Rubber is a 2010 French horror comedy film about a tire that comes to life and kills people with its psychic powers. It was directed and written by Quentin Dupieux. The film premiered at the 2010 Cannes Film Festival.

Duffy was seen in the Paramount feature Super 8, directed by filmmaker J. J. Abrams, produced by Steven Spielberg, and released on June 10, 2011, in both conventional and IMAX 3D theatres.