Thomas was born in Newark, New Jersey and was raised in Woodbridge, New Jersey. While attending Woodbridge High School, he played football, ice hockey, tennis and track and was active in drama and vocal music. He was originally a pre-law student at Ohio University, where he also played football and ice hockey. Duffy auditioned for an opera, was cast, and finally graduated with a BFA in acting. He was a member of Ohio's 1979 MCHL championship hockey team. He also was selected for the 1979 summer company of the Monomoy Theater, in Chatham, MA on Cape Cod.

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.

Other films Duffy completed in the 1990s were Independence Day, Mercury Rising, Poodle Springs, The Fan, The River Wild, Wolf, Out for Justice, The Mambo Kings and Let the Devil Wear Black.

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.

Duffy played Dr. Robert Burke in Steven Spielberg's 1997 blockbuster, The Lost World: Jurassic Park. He prepared for the role by watching Dr. Robert Bakker and traveled to Wyoming to work on a dig with Bakker.

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.

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.