Peppard secured a major role when he starred alongside Audrey Hepburn in Breakfast at Tiffany’s (1961), and later portrayed a character based on Howard Hughes in The Carpetbaggers (1964). On television, he played the title role of millionaire insurance investigator and sleuth Thomas Banacek in the early-1970s mystery series Banacek. He played Col. John “Hannibal” Smith, the cigar-smoking leader of a renegade commando squad, in the hit 1980s action show The A-Team.

Peppard made his stage debut in 1949 at the Pittsburgh Playhouse. After moving to New York City, Peppard enrolled in the Actors Studio, where he studied the Method with Lee Strasberg. He did a variety of jobs to pay his way during this time, such as working as a disc jockey, being a radio station engineer, teaching fencing, driving a taxi and being a mechanic in a motorcycle repair shop.

He worked in summer stock in New England and appeared at the open air Oregon Shakespeare Festival in Ashland, Oregon.

His first work on Broadway led to his first television appearance, with Paul Newman, in The United States Steel Hour (1956), as the singing, guitar-playing baseball player Piney Woods in Bang the Drum Slowly.

He made his film debut in The Strange One (1957).