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.