He was born in Nevada, Missouri, the son of the Canadian-born actor Walter Huston. He began his film career as a screenwriter and made films mainly from proven books or plays. The six-two, rail-thin director also acted in a number of films, with distinction in Otto Preminger's . He was also an accomplished painter who created the 1982 label for Château Mouton Rothschild, the French winery with whose chatelaine, Pauline de Rothschild, he reportedly had a brief affair in the 1940s.

A legendary Romeo (who, according to Paul Newman, "never talked about it"), the brown-eyed Huston was married to (1) Dorothy Harvey, (2) Lesley Black, (3) Evelyn Keyes, (4) Enrica Soma, and (5) Celeste Shane. All but the marriage to Soma, who died, ended in divorce. Among his children is the director Danny Huston and actress Anjelica Huston. In addition to Rothschild, his lovers included the actresses Nora Eddington, Olivia de Havilland, and Susan Tyrrell, and socialite Marietta Pea Tree. He was very friendly with fellow maverick director Orson Welles and author Ernest Hemingway.

He became an Irish citizen (although it is not clear if he had to relinquish his U.S. citizenship), and his daughter, Anjelica, attended school in Ireland for a number of years.

John Huston has the unique distinction of directing both his father Walter and his daughter Anjelica in Oscar-winning performances (in , respectively).

In the 1970s, he was a frequent actor in Italian B-films.

Although diagnosed with emphysema in 1978, Huston continued to smoke cigarettes until the end of his life. He died on August 28, 1987 following a severe attack of the lung disease and pneumonia, at the age of 81.

He is interred in the Hollywood Forever Cemetery in Hollywood, California.