George Peppard, Jr. was born in Detroit, Michigan, the son of building contractor George Peppard, Sr. and opera singer Vernelle Rohrer. He graduated from Dearborn High School in Dearborn, Michigan.

Peppard enlisted in the United States Marine Corps at 17 on July 8, 1946 and rose to rank of Corporal in the 10th Marines, leaving the Marines at the end of his enlistment in January 1948.

From 1948 to 1949, he studied Civil Engineering at Purdue University where he was a member of the Purdue Playmakers theatre troupe and Beta Theta Pi fraternity. He then transferred to Carnegie Institute of Technology (now Carnegie Mellon University) in Pittsburgh, Pennsylvania, where he received his bachelor's degree in 1955.

Peppard made his stage debut in 1949 at the Pittsburgh Playhouse. After moving to New York, Peppard enrolled in The Actors Studio, where he studied the Method with Lee Strasberg. His first work on Broadway led to his first television appearance, with a young Paul Newman, in The United States Steel Hour (1956). Peppard’s Broadway appearance in The Pleasure of His Company (1958) led to an MGM contract. Prior to a strong film debut in The Strange One (1957), he was discovered playing the illegitimate son of Robert Mitchum's character in the popular melodrama Home from the Hill (1960).

His good looks, elegant manner and superior acting skills landed Peppard his most famous film role as Paul Varjak in Breakfast at Tiffany's with Audrey Hepburn. This 1961 role boosted him briefly to a major film star. His leading roles in that film's wake included How the West Was Won in 1962, The Victors in 1963, The Carpetbaggers in 1964 and The Blue Max in 1966.

Peppard started choosing tough guy roles in big, ambitious pictures where he was somewhat overshadowed by ensemble casts; for example, his role as German pilot Bruno Stachel, an obsessively competitive officer from humble beginnings who challenges the Prussian aristocracy during World War I in The Blue Max (1966). For this role, Peppard earned a private pilot's license and did much of his own stunt flying, although stunt pilot Derek Piggott was at the controls for the famous under-the-bridge scene.

Due to Peppard's alcoholism, and notoriously difficult personality on the set, his career devolved into a string of B-movies through the late sixties and early seventies. He then had a notable success with the TV series Banacek (1972–74), (part of the NBC Mystery Movie series), and one of his most critically acclaimed, though rarely seen, performances in the TV movie Guilty or Innocent: The Sam Sheppard Murder Case (1975), as Sam Sheppard.

Among the disappointing films was the 1970 Western Cannon for Cordoba, in which Peppard played the steely Captain Rod Douglas, who has been put in charge of gathering a group of soldiers on a dangerous mission into Mexico, and 1967's Rough Night in Jericho in which he co-starred with crooner Dean Martin. Peppard appeared in the short-lived (half a season) Doctors' Hospital (1975) and several other television films. He was in the cult science fiction film Damnation Alley in 1977. With fewer interesting film roles coming his way, he acted in, directed and produced the drama Five Days from Home in 1979.

In a rare game show appearance, Peppard did a week of shows on Password Plus in 1979. Out of five shows, one was never broadcast on NBC (but aired much later on GSN) due to a rant where he expressed dissatisfaction with NBC executives watching "as if you're some sort of crook." Peppard was never asked to return to the show after his notorious outburst.[citation needed]

In 1981, Peppard was offered, and accepted, the role of Blake Carrington in the TV series Dynasty. During the filming of the pilot episode, which also featured Linda Evans and Bo Hopkins, Peppard repeatedly clashed with the show's producers, Richard and Esther Shapiro; among other things, he felt that his role was too similar to that of J.R. Ewing in the series Dallas. Three weeks later, before filming was to begin on additional episodes, Peppard was fired and the part was offered to John Forsythe; the scenes with Peppard were reshot.