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Film stardom at Biograph Studios (1912–1925)

After 10 years of acting on the stage, she made her film debut opposite Dorothy in Griffith's short film An Unseen Enemy (1912). At the time, established thespians considered "the flickers" a rather base form of entertainment, but she was assured of its merits. Gish continued to perform on the stage, and in 1913, during a run of A Good Little Devil, she collapsed from anemia. Lillian took suffering for her art to the extreme in a film career which became her obsession. One of the enduring images of Gish's silent film years is the climax of the melodramatic Way Down East, in which Gish's character floats unconscious on an ice floe towards a raging waterfall, her long hair and hand trailing in the water. Her performance in these frigid conditions gave her lasting nerve damage in several fingers. Similarly, when preparing for her death scene in La Bohème over a decade later, Gish reportedly did not eat and drink for three days beforehand, causing the director to fear he would be filming the death of his star, as well as of the character.

Lillian starred in many of Griffith's most acclaimed films, including The Birth of a Nation (1915), Intolerance (1916), Broken Blossoms (1919), Way Down East (1920), and Orphans of the Storm (1921). He utilized her expressive talents to the fullest, developing her into a suffering yet strong heroine. Having appeared in over 25 short films and features in her first two years as a movie actress, Lillian became a major star, becoming known as "The First Lady of American Cinema" and appearing in lavish productions, frequently of literary works such as Way Down East. She became the most esteemed actress of budding Hollywood cinema.

She directed her sister Dorothy in one film, Remodeling Her Husband (1920), when D. W. Griffith took his unit on location. He told Gish that he thought the crew would work harder for a girl. Gish never directed again, telling reporters at the time that directing was a man's job. The film is now thought to be lost.