Zerbe was born in Long Beach, California, the son of Catherine (née Scurlock) and Arthur LeVan Zerbe. He attended Pomona College in Claremont, California, graduating in 1958. His parents were also alumni of Pomona College.

Zerbe served in the United States Air Force from 1959-61.

Zerbe has been married to Arnette Jens (sister of Actress Salome Jens), since October 7, 1962; the couple has two children.

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. Trench in the private detective series Harry O. In 1981, he played eldest brother Benjamin Hubbard in a Broadway revival of The Little Foxes.

Zerbe's interest in acting was kindled by stage productions when he was 17. He studied at the Stella Adler Studio in New York City. On television, he has played guest roles on such series as Naked City, The Virginian, The Big Valley, Route 66, The Wild Wild West, Twelve O'Clock High, Bonanza, Mission: Impossible, Gunsmoke, Hawaii Five-O, Mannix, It Takes a Thief, The Chisholms, Ironside, The F.B.I., The Rookies, and Columbo, among others. He held a starring role in The Young Riders and co-starred on Harry O in that series' second and final seasons. Zerbe was also seen as Pontius Pilate in the miniseries A.D. and as General Grant in North and South: Book II. He was also in many episodes of the mini-series Centennial, in 1978. His latest appearance is in the 2013 American black comedy-crime film American Hustle.

Zerbe is the former artistic Director of Reflections, A New Plays Festival at the Geva Theatre in Rochester, New York, and has 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.