Fuller was born in Jonesboro, Georgia, near Atlanta. He was sent by his mother to live with foster parents when he was a young child, in a rural setting where he was badly mistreated. Growing up, he worked at numerous jobs: grazing cows for ten cents a day; working in a barrel factory, a broom factory, and a rock quarry; working on a railroad and for a streetcar company; shining shoes; and even peddling hand-carved wooden snakes. By the age of 10, he was playing the guitar in two techniques, which he described as "frailing" and "picking."
In the 1920s he lived in southern California, where he operated a hot-dog stand and was befriended by Douglas Fairbanks. He worked briefly as a film extra in The Thief of Bagdad (1924) and East of Suez. In 1929 he settled in Oakland, across the bay from San Francisco, where he worked for the Southern Pacific Railroad for many years as a fireman, spike driver, and maintenance-of-way worker. He married, and he and his wife, Gertrude, had a family. During World War II, he worked as a shipyard welder, but when the war ended he found it increasingly difficult to secure employment. Around the early 1950s, Fuller began to consider the possibility of making a living as a musician.
Up to this point, Fuller had never worked as a full-time professional musician, but he was an accomplished guitarist and he had carried his guitar with him and busked for money by passing the hat. He had a good memory for songs and had a large repertoire of crowd-pleasers in diverse styles, including country blues, work songs, ragtime and jazz standards, ballads, spirituals, and instrumentals. For a while, he operated a shoe-shine stand, where he sang and danced to entertain passersby. He began to compose songs, many of them based on his experiences on the railroads, and also reworked older pieces, playing them in his syncopated style. When he set out to make a career as a musician, he had difficulty finding reliable musicians to work with: thus his one-man band act was born, and he started calling himself "The Lone Cat."
Starting locally, in clubs and bars in San Francisco and across the bay in Oakland and Berkeley, Fuller became more widely known when he performed on television in both the Bay Area and Los Angeles. In 1958, at the age of 62, he recorded his first album, released by Good Time Jazz Records. Fuller's instruments included 6-string guitar (an instrument which he had abandoned before the beginning of his one-man band career), 12-string guitar, harmonica, kazoo, cymbal (high-hat) and fotdella. He could play several instruments simultaneously, particularly with the use of a headpiece to hold a harmonica, kazoo, and microphone. In addition, he would generally include at least one tap dance, soft-shoe, or buck and wing in his sets, accompanying himself on a 12-string guitar as he danced. His style was open and engaging. In typical busker's fashion, he addressed his audiences as "ladies and gentlemen," told humorous anecdotes, and cracked jokes between songs. He told of his love of his wife and family, but some of his stories were anything but cheerful, often including recapitulations of his tragic childhood, his mother's illness and early death, his determination to escape the segregated racial system of the South, suicide, and death.
The British label Topic Records issued his album Working on the Railroad in 1959 as a 10-inch vinyl LP, including "San Francisco Bay Blues". This recording is included as track six on the first CD of the Topic Records 70-year anniversary boxed set Three Score and Ten.
The fotdella was a musical instrument of Fuller's own creation and construction. He built at least two of them, in slightly different patterns, as evidenced in photographs and film footage of his performances.
As a one-man band, Fuller wanted to supply a more substantial accompaniment than the typical high-hat (cymbal) or bass drum used by other street musicians. His solution was the fotdella, a foot-operated percussion bass, consisting of an upright wood box, shaped like the top of a double bass, with a short neck at the top, and six piano bass strings attached to the neck and stretched down over the body. The strings were played by means of six piano or organ pedals, each connected to a padded piano hammer which struck a string. Removing his shoe and placing his sock-covered foot in a rotating heel cradle, Fuller played the six pedals of the fotdella like a piano. With the instrument's six notes, he could play bass lines in several keys. He occasionally played without it, if a song exceeded its limited range.
The name was coined by his wife, who took to calling the instrument a "foot-diller" (a "killer-diller" instrument played with the foot), which was shortened to fotdella. The term foot piano has been used by some performers and musicologists to describe this type of instrument.
Fuller died in January 1976 in Oakland, California, from heart disease, at the age of 79. He was interred at Evergreen Cemetery, in Oakland. His fotdella and his 1962 Silvertone Electric-Acoustic guitar (the latter purchased from a Sears and Roebuck store in Detroit to replace his Maurer guitar, which had been stolen while he was on tour) are in the possession of the Smithsonian Institution.
Bob Dylan covered Fuller's "You're No Good" on his debut album in 1962. According to his biographer David Dalton, Dylan borrowed the idea of using a harmonica rack from Fuller and imitated Fuller's "gravelly vocal style."
Fuller's songs have also been covered by Johnny Cash ("The Legend of John Henry"), Grateful Dead ("The Monkey and the Engineer" and "Beat It On Down the Line"), Hot Tuna, Peter, Paul and Mary, Janis Joplin, Jim Croce ("San Francisco Bay Blues"), Don Partridge ("San Francisco Bay Blues", "Working on the Railroad" and "Stealin' Back to My Old Time Used to Be"), Glenn Yarbrough, Richie Havens, Eric Clapton, Paul McCartney, T. Nile, Dan the One Man Band, Mungo Jerry, Tim O'Brien & Hot Rize ("99 Years and One Dark Day"), Punch Brothers, and Dave Rawlings Machine ("Monkey and the Engineer").
During Fuller's UK tour in 1965, Don Partridge booked him for a sold-out concert in Ealing and was so influenced by Fuller that he developed his own stand-up one-man band concept for street busking in the UK, later leading to his pop success.