His father owned a hardware store and had hoped he would take over the business, but he was an ambitious youth and aimed to become an architect, winning a place at Princeton. There he got his first taste of acting with the University Players, as well as playing the accordion for the Triangle Club and participating in the male-only cheerleading squad. After graduating in 1932 he moved to New York City with his best friend, Henry Fonda, and succeeded in winning a small role in the Broadway comedy hit ’Goodbye Again’.

This led to bigger parts in ‘Page Miss Glory’ and Sidney Howarth's ‘Yellow Jack’ which in turn drew him to the attention of the Hollywood studios. In 1935, Stewart was signed to MGM, who were convinced of his potential despite his initial awkwardness onscreen. An early appearance in Tim Whelan's The Murder Man, alongside Spencer Tracy and Virginia Bruce, proved disappointing, but within a year he was ready to take the lead in films such as  After the Thin Man, with William Powell and Myrna Loy, whom he adored. Demonstrating his adaptability early on (his ability to cross genres would become a hallmark of his career), he achieved major public popularity with the 1938 romantic comedies Vivacious Lady, with Ginger Rogers, and Made for Each Other, with Carole Lombard.  

He spent two years making training and promotional films for them before finally getting the chance to fly, taking B-24 bombers over Germany under the command of Sergeant Walter Matthau. His actions in combat won him two Distinguished Flying Crosses and by the end of the war he had risen to the rank of colonel. Upon returning to Hollywood, Stewart continued to pursue his eclectic approach to cinema, starring alongside a giant white rabbit in Harvey as well as appearing in more conventional classics like Rope  and Broken Arrow. The former of these represented the start of a long-running collaboration with Alfred Hitchcock, which produced  Rear Window, with Grace Kelly; The Man Who Knew Too Much, with Doris Day; and  Vertigo, with Kim Novak.  

He retired from acting in 1992 and was granted a retirement promotion to Major General by his former co-star Ronald Reagan. Already stricken by personal tragedy when his son died in Vietnam, he never really recovered from his wife's death from lung cancer, and he died of a heart attack on July 2, 1997.