Born George William Crisp in London, he began his film acting career in 1908, and appeared in D. W. Griffith's The Birth of a Nation in 1915. During the silent film era, he also directed comedy films, and dramas such as the 1916 version of Ramona. Although he directed his last film in 1930, the Directors Guild of America voted him a Life Member Award in 1957.

With the advent of talking pictures, Crisp established a career as a versatile character actor, and won the Academy Award for Best Supporting Actor for his memorable role as the Welsh father in How Green Was My Valley (1941).

His more than 150 films include Her Awakening (1913), Broken Blossoms (1919), The Black Pirate (1926), Mutiny on the Bounty (1935), The Charge of the Light Brigade (1936), The Life of Emile Zola (1937), Jezebel (1938), Wuthering Heights (1939), The Private Lives of Elizabeth and Essex (1939), Knute Rockne, All American (1940), Shining Victory (1941), Lassie Come Home (1943), The Uninvited (1944), National Velvet (1944)The Valley of Decision (1945) Pollyanna (1960), Greyfriars Bobby (1961), and Spencer's Mountain (1963)

He was married to the screenwriter Jane Murfin from 1932 until 1944.

For his contribution to the motion picture industry, Donald Crisp has a star on the Hollywood Walk of Fame at 1620 Vine St.

Donald Crisp died from a cerebral haemorrhage in Van Nuys, California and was interred in the Forest Lawn Memorial Park Cemetery in Glendale, California.