Holden became a star with his first substantial feature role as the boxer-violinist in "Golden Boy" (1939), a part that cast him opposite screen siren Barbara Stanwyck, who would later become his mentor and life-long booster. Holden was soon getting cast in fairly innocuous roles: the boy-next-door; the quintessential All-American in such films as "Arizona" as the amiable lover of a determined corruption buster Jean Arthur; the idealistic small town hero in "Our Town"; a hell-raising Joe College in "Those Were the Days" (all 1940). He was pitted against Glenn Ford, rivaling for the affections of Claire Trevor, in "Texas" (1941), tried to heat up an ice-cool Dorothy Lamour in the musical "The Fleet's In" (1942), and was a poor boy who gets married in "Meet The Stewarts" (1942).

Holden joined the Air Force, fought in WWII and returned to the screen with a more complex personality. He starred in several films which, though unremarkable, were box-office favorites ("Dear Ruth" 1947 and "Rachel and the Stranger" 1948) before being cast against type to play a psycho killer in the low-budget noir "The Dark Past" (1949). 1950 proved to be Holden's watershed year: he starred in two career landmarks, "Born Yesterday" as Judy Holliday's culture tutor-cum-lover, and Billy Wilder's "Sunset Boulevard", as Norma Desmond's hack screenwriter gigolo. With the latter portrayal, Holden's screen persona began to move into the gray areas that were further explored in later roles like that of the pessimistic POW suspected of being a Nazi informer in Wilder's "Stalag 17" (1953), a role which garnered Holden a Best Actor Oscar. Wilder discovered and expertly exploited the dichotomy between the actor's wholesome All-American appearance and his potential for conveying moral darkness. Holden went on to become a leading box-office star between 1954-58 and reigned as the top-grosser in 1956. Notable roles of this period included playing an ambitious company man in "Executive Suite", a ne'er-do-well playboy in Wilder's "Sabrina" (both 1954) and the drifter who breaks Kim Novak's heart in "Picnic" (1956).

Holden remained active for nearly three more decades, showing up in a pivotal role in "The Bridge on the River Kwai" (1957). While many of his 60s credits were routine and worse (e.g. "Paris When It Sizzles" 1963), the decade also boasted some undeniable triumphs, including his portrayal of a double agent in the fine thriller "The Counterfeit Traitor" (1962) and a career highlight in Peckinpah's "The Wild Bunch" (1969). The 70s found Holden in a number of mediocre action and adventure vehicles ("Towering Inferno" 1974, "Ashanti" 1979, "The Earthling" 1980) as well as a few winners including the highly acclaimed "Network" (1976), as a conscientious TV executive, and Wilder's sadly underrated "Fedora" (1978), as a producer trying to encourage a Garbo-esque star to come out of self-imposed retirement. Fairly late in his career, Holden made his TV debut, winning an Emmy for his work in the detective miniseries about the L.A. police department "The Blue Knights" (1973). His final film performance came in Blake Edwards' caustically comic look at Hollywood, "S.O.B." (1981).

Holden died from an accidental fall in his apartment in 1981.