Lee began his career as a chemical engineer but grew dissatisfied after four years in manufacturing. Encouraged by his first wife, artist Doris Emrick, Lee began to paint. The Lees left the Midwest for San Francisco, where Doris wanted to study. They arrived just before the 1929 crash of the stock market and the onset of the Depression and immediately became engaged in the thriving art community there. From San Francisco, the Lees next moved to the New York art colony of Woodstock, where they lived in the summers from 1931 to 1936, spending their winters in New York City. In 1935 Lee began to experiment with a camera as an aid to his painting and soon gave up painting in favor of photography. He and Doris went to Europe, where she studied art and he traveled, observing life in Eastern Europe, Germany, and the Soviet Union.
In 1935 Lee began to photograph miners and record conditions in Pennsylvania coalmines. His growing interest in social issues and his affinity for photography as a means of recording social conditions brought him in contact with other visual artists, among them Pare Lorentz and Ben Shahn, whose work he admired. He heard that Shahn was involved with the documentation program of the Historic Division of the Resettlement Administration, later renamed the Farm Security Administration, and decided to seek a job there. His first assignment for Roy Stryker was to photograph the Jersey Homesteads housing project in 1936. When Carl Mydans left the agency, Stryker offered Lee a full-time job.
Russell Lee's photographic work continues to be associated with the documentary tradition and the work of the Farm Security Administration under the direction of Roy Stryker. As part of the team that also included Dorothea Lange, Arthur Rothstein and Walker Evans, Lee's primary task was to document rural communities with the goal of making urban Americans aware of the plight of tenant farmers, sharecroppers, and migrant workers stricken by drought and the Great Depression. Stryker assigned Lee to cover the Midwest and the West Coast, where he typically stayed on the road much longer than expected. Lee made some of his better-known early photographs in rural Iowa in 1936. He traveled throughout Texas and New Mexico between 1939 and 1940. Lee and his first wife grew apart during this time and divorced in 1938. During the 1940's, Lee's distinctive work appeared in hundreds of newspapers and popular journals including Life, Look, Fortune, U.S. Camera, and Survey Graphic.
Shortly after the U.S. entered Word War II, the Historical Division transferred to the jurisdiction of the Office of War Information. Lee left the FSA group and joined the Air Transport Command as a captain in January of 1943, assigned to take aerial surveillance photographs as well as documenting local conditions on the ground. When the war ended, Russell Lee resigned his commission and in 1947 he and his second wife Jean Smith moved to Austin, Texas. From 1965 to 1973 he taught photography at the University of Texas. Although Lee often traveled as a free-lance photographer on assignment for magazines, corporations, the federal government, and the University, Austin remained his home and Texas a major focus of his work until his death in 1986.