When Griffith was 14, his mother abandoned the farm and moved the family to Louisville, Kentucky; there she opened a boarding house, which failed shortly afterward. Griffith then left high school to help support the family, taking a job in a dry goods store and later in a bookstore. He began his creative career as an actor in touring companies. Meanwhile, he was learning how to become a playwright, but had little success—only one of his plays was accepted for a performance. He traveled to New York City in 1907 in an attempt to sell a script to Edison Studios producer Edwin Porter; however, Porter rejected the script, but gave him an acting part in Rescued from an Eagle’s Nest instead. He then decided to become an actor and appeared in many films as an extra.

In 1908, Griffith accepted a role as a stage extra in Professional Jealousy for the American Mutoscope and Biograph Company, where he met cameraman Billy Bitzer, and his career in the film industry changed forever. In 1908, Biograph’s main director Wallace McCutcheon, Sr. grew ill, and his son Wallace McCutcheon, Jr. took his place. McCutcheon, Jr. did not bring the studio success; Biograph co-founder Harry Marvin gave Griffith the position, and he made the short The Adventures of Dollie. He directed a total of 48 shorts for the company that year.

Among the films he directed in 1909 was The Cricket on the Hearth, an adaptation of Charles Dickens’ novel. On the influence of Dickens on his own film narrative, Griffith employed the technique of cross-cutting—where two stories run alongside each other, as seen in Dickens’ novels such as Oliver Twist. When criticized by a cameraman for doing this in a later film, Griffith was said to have replied, “Well, doesn’t Dickens write that way?”.

Griffith directed and produced The Clansman through Reliance-Majestic Studios in 1915, which became known as The Birth of a Nation and is considered one of the early feature length American films. The film was a success, but it aroused much controversy due to its depiction of slavery, the Ku Klux Klan and race relations in the American Civil War and the reconstruction era of the United States. It was based on Thomas Dixon, Jr.’s 1905 novel The Clansman: A Historical Romance of the Ku Klux Klan; it depicts Southern slavery as benign, the enfranchisement of freedmen as a corrupt plot by the Republican Party, and the Ku Klux Klan as a band of heroes restoring the rightful order. This view of the era was popular at the time and was endorsed for decades by historians of the Dunning School, although it met with strong criticism from the National Association for the Advancement of Colored People (NAACP) and other groups.

Griffith’s production partnership was dissolved in 1917, and he went to Artcraft, part of Paramount Pictures, and then to First National Pictures (1919–1920). At the same time, he founded United Artists together with Charlie Chaplin, Mary Pickford and Douglas Fairbanks; the studio was premised on allowing actors to control their own interests rather than being dependent upon commercial studios.

In 1936, director Woody Van Dyke, who had worked as Griffith’s apprentice on Intolerance, asked Griffith to help him shoot the famous earthquake sequence for San Francisco, but did not give him any film credit. Starring Clark Gable, Jeanette MacDonald and Spencer Tracy, it was the top-grossing film of the year.

In 1939, the producer Hal Roach hired Griffith to produce Of Mice and Men (1939) and One Million B.C. (1940). He wrote to Griffith: “I need help from the production side to select the proper writers, cast, et cetera, and to help me generally in the supervision of these pictures.”

Although Griffith eventually disagreed with Roach over the production and parted, Roach later insisted that some of the scenes in the completed film were directed by Griffith. This would make the film the final production in which Griffith was actively involved. However, cast members’ accounts recall Griffith directing only the screen tests and costume tests. When Roach advertised the film in late 1939 with Griffith listed as producer, the latter asked that his name be removed.

Although mostly forgotten by movie-goers of the time Griffith was held in awe by many in the film industry. In the mid-1930s he was given a special Oscar by the Academy of Motion Picture Arts and Sciences. In 1946 he made an impromptu visit to the film location of David O. Selznick’s epic western Duel in the Sun, where some of his veteran actors, Lillian Gish, Lionel Barrymore and Harry Carey, were cast members. Gish and Barrymore found their old mentor’s presence distracting and became self-conscious so, when the two were filming their scenes, Griffith hid behind the scenery.

On the morning of July 23, 1948, Griffith was discovered unconscious in the lobby at the Knickerbocker Hotel in Los Angeles, where he had been living alone. He died of a cerebral hemorrhage at 3:42 PM on the way to a Hollywood hospital. A public memorial service was held in his honor at the Hollywood Masonic Temple, but few stars came to pay their last respects. He is buried at Mount Tabor Methodist Church Graveyard in Centerfield, Kentucky. In 1950, The Directors Guild of America provided a stone and bronze monument for his grave site.