Reared in poverty in St. Louis, Gregory began working at an early age to help support his family. He was involved in sports and social causes in high school, and he entered Southern Illinois University on an athletic scholarship in 1951, excelling as a middle-distance runner. He was named the university's outstanding student athlete in 1953, the same year he left college to join the U.S. Army, where he hosted and performed comedy routines in military shows.

After a brief return to his alma mater in 1955-56, Gregory sought entrance to the national comedy circuit in Chicago. His breakthrough came in 1961, when a one-nighter at the Chicago Playboy Club turned into a six-week stint that earned him a profile in Time magazine and a television appearance on “The Jack Paar Show.” In his numerous subsequent television, nightclub, and concert routines, he targeted poverty, segregation, and racial discrimination. Active in the Civil Rights Movement, he participated in numerous demonstrations and was arrested for civil disobedience several times; in 1963 he was jailed in Birmingham, Ala. His activism spurred him to run for mayor of Chicago in 1966 and for president of the United States in 1968.

In the early 1970s Gregory abandoned comedy to focus on his political interests, which widened from race relations to include such issues as violence, world hunger, capital punishment, drug abuse, and poor health care. He generated particular attention for his many hunger fasts. At this time he became a vegetarian, a marathon runner, and an expert on nutrition. He soon began a successful business venture with his nutritional product, the “Bahamian Diet,” around which he built Dick Gregory Health Enterprises, Inc. Through his company, he targeted the lower life expectancy of black Americans, which he attributed to poor nutrition and drug and alcohol abuse.

Gregory wrote many books, including Nigger: An Autobiography (1964) and No More Lies: The Myth and the Reality of American History (1971). He made a brief return to the comedy circuit in the mid-1990s.