White left high school in her second year to join a local theatrical stock company, and at age 18 she joined a traveling theatrical troupe. In 1910, when her voice began to fail, she decided to seek a career in films and joined the Powers Film Company in the Bronx, New York City. In the next 13 years she made more than 100 comedies, serials, and westerns.

White was first known for her work in short slapstick comedies such as The Girl in the Next Room and Her Dressmaker's Bill. In 1914 she starred in a 20-episode serial for the American branch of the French film company Pathé Frères. The Perils of Pauline was the most successful example of its genre—the short-episode serial that emphasized suspense, danger, and the cliff-hanger ending that aimed at bringing the audience back for the next sequel. The Perils of Pauline made White an international movie star whose fame for a while eclipsed even that of Mary Pickford (Pickford, Mary). Among the other serials she made were The Exploits of Elaine (1914–15), The Iron Claw (1916), and The Black Secret (1919–20). The serials featured the heroine performing a variety of acrobatic stunts by way of escaping sundry perils. White performed many of the stunts herself; although studio publicity claimed she performed them all, stuntmen were used frequently for the dangerous ones.

In the 1920s, with the rise of the feature film, serials lost popularity, and White failed in her attempt to make the transition to the new genre. After 1923 she lived in Paris. She had earned an estimated $2 million in her short but arduous career, and she invested it wisely. She made one more film in Paris, Terror (released as Perils of Paris in the United States), before retiring to a life of luxury. It was thought that a spinal injury suffered in a fall during the filming of The Perils of Pauline may have hastened her early death in 1938.