"Big Bill" was born William Lee Conley Broonzy in Scott County, Mississippi on 26 June 1893 or 1898 (the exact year is unclear). While Broonzy himself claimed to be born in 1893, another source[citation needed] claims that Broonzy had a twin sister named Lannie Broonzy who had proof they were born on 26 June 1898. During this time, it was common for black men to add years to their actual age in order to get a job or join the military, which may very well have been Broonzy's case as well. Regardless, Broonzy left Mississippi in 1924 and arrived in Chicago, where he met Papa Charlie Jackson, who taught him to play guitar (Broonzy had previously been a fiddler). Broonzy first recorded as a self-accompanied singer in 1929, and continued to record in that style. Around 1936, he became one of the first blues singers to use a small instrumental group, including "traps" (drums) and acoustic bass as well as one or more melody instruments (horns and/or harmonica). These discs were usually issued as Big Bill and his Chicago Five. At that time, Broonzy was recording for the American Record Corporation on their line of less expensive labels (Melotone, Perfect Records, et al). In 1939, ARC was acquired by CBS, and Broonzy then appeared on Vocalion (later Okeh) and, after 1945, on Columbia Records. One of his best-known songs was written at that time, "Key To the Highway". During much of his life he worked as a Pullman porter, cook, foundry worker and custodian to supplement his income.

During this time, Broonzy usually played South Side clubs, and also toured with Memphis Minnie during the 1930s. When the second American Federation of Musicians strike ended in 1948, Broonzy was picked up by the Mercury label, for whom he made a handful of records through to 1951. After that, Broonzy returned to his solo folk-blues roots, and traveled extensively (and recorded) across Europe into early 1956. Although he had been a pioneer of the Chicago blues style and had employed electric instruments as early as 1942, his new, white audiences wanted to hear him playing his earliest songs unaccompanied on acoustic guitar, considering those to be more "authentic". Broonzy returned to Chicago in 1956 and continued to perform. Studs Terkel, Win Stracke and Broonzy worked in a touring folk music review called I Come for to Sing. Broonzy was one of the founding faculty members at the Old Town School of Folk Music. Terkel called him the key figure in this group. He was present on opening night of the school and taught the first class how to play his song, "The Glory of Love".

Broonzy died of throat cancer in 1958, and is buried in Lincoln Cemetery, Blue Island, Illinois. During his folk-blues period, he recorded with Pete Seeger, Sonny Terry, Brownie McGhee, and Leadbelly. A considerable portion of his early ARC/CBS recordings have been reissued in anthology collections by CBS-Sony; as well, other earlier recordings have been collected on blues reissue labels, as have his later European and Chicago recordings of the fifties.

Since Broonzy was never a spectacular electric guitarist in the manner of others of his early-fifties contemporaries, he is not as well known as others of that period, and was not extensively covered during the "British Blues Revival" of the sixties; however, he did gain some popularity, with "Key to the Highway" featured on Derek and the Dominos' album, Layla and Other Assorted Love Songs. He was an acclaimed acoustic guitar player, and a major source of inspiration to men like Muddy Waters, Memphis Slim, and Ray Davies.

In Q-Magazine (September 2007) it is mentioned that Ron Wood of The Rolling Stones has a Bill Broonzy track as his favorite when it comes to guitar music. The track is "Guitar Shuffle". "It was one of the first tracks I learnt to play, but even to this day I can't play it exactly right".

Big Bill Broonzy recorded over 350 compositions