Born in Portland, Oregon on April 12, 1883, Cunningham's family moved to Seattle in 1889. Inspired by Gertrude Kasebier's work, she purchased her first camera in 1901. After studying chemistry and botany at the University of Washington, she worked for the Edward S. Curtis Studio, Seattle, from 1907 to 1909. Receiving a scholarship, Cunningham studied for a year at the Technische Hochschule, Dresden.
Upon her return to Seattle in 1910, she opened a studio and had the first major exhibition of her work at the Brooklyn Institute of Arts and Sciences in 1912.
In 1915, Cunningham married printmaker Roi Partridge and gave birth to her first son, Gryffyd. Two years later, her family moved to California, where she gave birth to twin sons, Padraic and Rondal. In 1920, the family moved to Oakland, where her husband taught at Mills College. During the 1920s, she exhibited her art work and began photographing plant forms.
Along with Ansel Adams, John Paul Edwards, Sonya Noskowiak, Henry Swift, Willard Van Dyke, and Edward Weston, Cunningham formed the f/64 Group, a society of purist photographers in 1932. During the same year she began working for Vanity Fair and other magazines and began a career as a portrait photographer, including Martha Graham, Cary Grant, Morris Graves, Alfred Stieglitz, and Spencer Tracy as her subjects. She divorced her husband in 1934.
In 1947, Cunningham established a studio in her San Francisco home, and continued to exhibit extensively until her death on June 24, 1976.