His notable film roles include the post-apocalyptic cult leader Matthias in The Omega Man, a 1971 film adaptation of Richard Matheson's 1954 novel, I Am Legend; as an Irish Catholic coal miner and one of the Molly Maguires in the 1970 film The Molly Maguires; as a corrupt gambler in Farewell, My Lovely; as the leper colony chief Toussaint in the 1973 historical drama prison film Papillon; as Abner Devereaux in Kiss Meets the Phantom of the Park; as villain Milton Krest in the James Bond film Licence to Kill; Rosie in The Turning Point; Roger Stuart in The Dead Zone; Admiral Dougherty in Star Trek: Insurrection; and Councillor Hamann in The Matrix Reloaded and The Matrix Revolutions.

He made his New York City stage debut at the Greenwich Mews Theatre on October 15, 1961 with The Cave Dwellers.

He co-starred on Harry O from the second half of the first season through the series' conclusion at the end of the second season as Lieutenant Trench, known for his stentorian baritone, alternately heard yelling for his underling, Sergeant Roberts, or, at a lower decibel, horse-trading for information with the title character, P.I.

[8] Zerbe is the former artistic director of Reflections, A New Plays Festival at the Geva Theatre in Rochester, New York, and toured the United States, in 1981, with Behind the Broken Words, a performance of contemporary poetry, comedy, and dramatic works with fellow actor Roscoe Lee Browne.

[9] In 1976, Zerbe won an Emmy Award for Outstanding Continuing Performance by a Supporting Actor in a Drama Series for his role as Lieutenant K.C.