Born in Wichita, Kansas, Smith graduated from Wichita North High School in 1936. He began his career by taking pictures for two local newspapers, the Eagle (morning circulation) and the Beacon (evening circulation). He went to New York City and began work for Newsweek and became known for his incessant perfectionism and thorny personality. Smith was fired from Newsweek for refusing to use medium format cameras and joined Life Magazine in 1939. He soon resigned from Life and was wounded in 1942 while simulating battle conditions for Parade magazine.
As a correspondent for Ziff-Davis Publishing and then Life again, Smith entered World War II on the front lines of the island-hopping American offensive against Japan, photographing U.S. Marines and Japanese prisoners of war at Saipan, Guam, Iwo Jima, and Okinawa. On Okinawa, Smith was hit by mortar fire. After recovering, Smith continued at Life and perfected the photo essay from 1947 to 1954. In 1950, he was sent to the United Kingdom to cover the General Election, in which the Labor Party (UK), under Clement Attlee, was narrowly victorious. Life had actually taken an editorial stance against the Labor government, but Smith's essay was very sympathetic to Attlee. In the end, a limited number of Smith's photographs of working-class Britain were published, including three shots of the South Wales valleys. In a documentary made by BBC Wales, Professor Dai Smith traced a miner who described how he and two colleagues had met Smith on their way home from work at the pit and had been instructed on how to pose for one of the photos published in Life.
Smith severed his ties with Life again over the way in which the magazine used his photographs of Albert Schweitzer. Upon leaving Life, Smith joined the Magnum photo agency in 1955. There he started his project to document Pittsburgh. This project consisted of a series of book-length photo essays in which he strove for complete control of his subject matter. Complications from his consumption of drugs and alcohol led to a massive stroke, from which Smith died in 1978.
Smith was perhaps the originator and arguably the master of the photo-essay. In addition to Pittsburgh, these works include Nurse Midwife, Minamata, Country Doctor, and Albert Schweitzer - A Man of Mercy.
Today, Smith's legacy lives on through the W. Eugene Smith Memorial Fund to promote "humanistic photography." Since 1980, the fund has awarded photographers for exceptional accomplishments in the field.