Burns began his career at age seven as a singer in the PeeWee Quartet and later performed as a dancer, skater, and comic. He met Allen in the early 1920s, and they married in 1926. Beginning in 1933 Burns and Allen headlined their own show on American radio for 17 years, playing fictional versions of their real-life selves. They also achieved success in movies during the 1930s in such films as The Big Broadcast (1932), International House (1933), Six of a Kind (1934), Love in Bloom (1935), and College Swing (1938). A Damsel in Distress (1937) provided the team with their best screen roles; the film is particularly memorable for two intricate dance routines performed by Burns, Allen, and Fred Astaire (Astaire, Fred).

The team's popularity began to wane after World War II, but it was revived when Burns decided to change their long-standing radio characterizations of young lovers to those of middle-aged spouses. They retained the domesticized approach for their television series, The George Burns and Gracie Allen Show (1950–58), which featured the innovative gimmick of Burns functioning as a one-man Greek chorus, frequently breaking the “fourth wall” to address the viewing audience. The show maintained its popularity for eight seasons and ended when Allen, plagued by ill health and stage fright, retired from performing.

Burns carried on for a few years with a succession of other female partners, but all (including Carol Channing) were unfavourably compared to Allen. Upon Allen's death in 1964, Burns concentrated mostly on producing television shows for several years. The death of his close friend Jack Benny (Benny, Jack) in 1974 unexpectedly precipitated Burns's comeback when he took over the role intended for Benny in the screen adaptation of Neil Simon's The Sunshine Boys (1975). His sensitive and wryly comic turn as vaudeville veteran Al Lewis earned him an Academy Award for best supporting actor. Burns was a headline star once again and embarked on a second career in which his new persona of a wise, witty, and slightly lecherous octogenarian proved enormously popular with film and nightclub audiences. He played the title role in the hit comedy Oh, God! (1977) and delivered what is perhaps his finest screen performance in Going in Style (1979). He kept active with club appearances and TV commercials until several months before his death at age 100. In his later years he was once asked if he believed in heaven and hell and replied, “I don't know what they've got, but I'm bringing my own music.”