Woodbridge Strong Van Dyke II was born on March 21, 1889 in San Diego, California. His father was a Superior Court judge who died the day his son was born. His mother, Laura Winston, returned to her former acting career. As a child actor, Van Dyke appeared with his mother on the vaudeville circuit with traveling stock companies. They traveled the west coast and into the Middle West. When he was five years old, they appeared at the old San Francisco Grand Opera House in Blind Girl. He would later remember his unusual education,

When Van Dyke was fourteen years old, he moved to Seattle to live with his grandmother. While attending Business school, he worked several part-time jobs, including janitor, waiter, salesman, and railroad attendant. Van Dyke's early adult years were unsettled, and he moved among jobs. In 1909, he married Actress Zelda Ashford, and the two joined various touring theater companies, finally arriving in Hollywood in 1915.

In 1915, Van Dyke found work as an assistant Director to D. W. Griffith on the film The Birth of a Nation. The following year, he was Griffith's assistant Director on Intolerance. That same year he worked as an assistant Director to James Young on Unprotected (1916), The Lash (1916), and the lost film Oliver Twist, in which he also played the role of Charles Dickens.

In 1917, Van Dyke directed his first film, The Land of Long Shadows for Essanay Studios. That same year he directed five other films: The Range Boss, Open Places, Men of the Desert, Gift O' Gab, and Sadie Goes to Heaven. In 1927, he traveled to Tacoma to direct two silent films for the new H.C. Weaver Productions: Eyes of the Totem and The Heart of the Yukon (the latter is considered a lost film).

His other films include the island adventure White Shadows in the South Seas (1928), its follow up: The Pagan (1929), Trader Horn (1931) filmed almost entirely in Africa, Tarzan the Ape Man (1932), Manhattan Melodrama (1934), and Marie Antoinette (1938). He is perhaps best remembered for directing Myrna Loy and william Powell in four Thin Man films: The Thin Man (1934), After the Thin Man (1936), Another Thin Man (1939), and Shadow of the Thin Man (1941); and Jeanette MacDonald and Nelson Eddy in six of their greatest hits, Naughty Marietta (1935), Rose Marie (1936), Sweethearts (1938), New Moon (1940) (uncredited because halfway through filming Robert Z. Leonard took over), Bitter Sweet (1940), and I Married an Angel (1942).

Many of his films were huge hits and top box office in any given year. He received Academy Award for Best Director nominations for The Thin Man (1934) and San Francisco (1936). He also directed the Oscar-winning classic Eskimo (also known as Mala the Magnificent), in which he also has a featured acting role.

A devout Christian Scientist, Van Dyke refused most medical care during his last years. After finishing his last film, he said his goodbyes to his wife, children, and studio boss Louis B. Mayer and then committed suicide on February 5, 1943, in Brentwood, Los Angeles. At his request, Jeanette MacDonald and Nelson Eddy both sang and officiated at his funeral.

On February 8, 1960, Van Dyke received a star on the Hollywood Walk of Fame for his contribution to Motion Pictures, at 6141 Hollywood Boulevard.