He is primarily known as a dramatic actor, including his role as the overzealous Sheriff Will Teasle in the 1982 hit movie First Blood, as Willy Loman in Arthur Miller's Death of a Salesman and in Cocoon (1985). He also has acted in several comedies, including the Chris Farley/David Spade movie Tommy Boy. He is also known for his role in F/X and F/X 2.

On stage, Dennehy made his Broadway debut in 1995 and in 1999 was the first male actor to be voted the Sarah Siddons Award for his work in Chicago theatre.

Dennehy joined the United States Marines in 1959 and served until 1963. In 1989, he became one of many Veteran(s) with Disputed Status when he told the New York Times that he claimed that he received shrapnel wounds in the Vietnam War. In 1993, he told Playboy that he served five years in Vietnam. However, his only overseas tour was to Okinawa. He apologized for his false claims in 1999.

During the 1980s, Dennehy gradually became a valuable supporting player in mainstream films and subsequently gained leading man status in the quirky thriller Best Seller where he appeared alongside James Woods to memorable effect. Brian played a role in the Gary Sinise directed farm epic Miles from Home in 1988. He gained his arthouse spurs during the same year when he starred in the Peter Greenaway movie The Belly of an Architect. Commenting upon this unusual venture, Dennehy said, "I've been in a lot of movies but this is the first film I've made."

After his TV performance as John Wayne Gacy in the chilling TV mini-series To Catch A Killer, Dennehy starred in other TV movies, including several outings as maverick cop Jack Reed. He was nominated for an Emmy Award for his 1993 performance in Murder in the Heartland. However, his huge success in 1996 playing Willy Loman indicated that he was as powerful an actor on stage as he had been in movies.

He was parodied in South Park: Bigger, Longer & Uncut.

Brian Dennehy is currently a resident of Woodstock, Connecticut.

In the episode "Jaws Wired Shut" of the show The Simpsons it is revealed by Apu that the Indian equivalent of Dennehy is an actor known as Otom Shank.