Alonzo "Lonnie" Johnson was born in New Orleans on February 8, 1899, into a family of musicians. He studied violin, piano and guitar as a child and picked up other instruments, among them the mandolin, but he concentrated on guitar for the whole of his professional career. In 1917 he joined a revue that toured England. When he came home in 1919 he found that every member of his family except his brother James had died in the influenza epidemic of 1918. The brothers settled in St. Louis in 1921 and worked as a duo, and Johnson also played on riverboats and in the orchestra of Charlie Creath.

In 1925 he won a blues contest at the Booker T. Washington Theatre in St. Louis, and the prize was a recording contract with Okeh. Between 1925 and 1932 he made about 130 recordings for the label, most of them blues vocals, and he became one of Okeh's best-selling artists. He recorded in New York with blues singers such as Victoria Spivey and the country blues singer Texas Alexander, and he toured with Bessie Smith in 1929. His wife Mary, whom he married in 1925, began a blues career of her own; the couple never recorded together and divorced in 1932. Alongside the vocal records, Okeh also let him record guitar solos and duets, and it used him as a guest on its jazz sessions, which is the side of his work that most reaches jazz listeners.

In December 1927 he joined Louis Armstrong's Hot Five in Chicago, paired with the banjoist Johnny St. Cyr, and played on "I'm Not Rough," "Savoy Blues" and "Hotter Than That." In 1928 he recorded "Hot and Bothered," "Move Over" and "The Mooche" with Duke Ellington for Okeh, and he also recorded with McKinney's Cotton Pickers under the name the Chocolate Dandies. His guitar duets with Eddie Lang, made for Okeh between 1928 and 1929, are regarded as among the earliest integrated jazz recordings: Lang, who was white, was billed as Blind Willie Dunn on the label's race series, the writing was credited to "Johnson-Dunn," and the pair also recorded with King Oliver as Blind Willie Dunn and His Gin Bottle Four. After the Bessie Smith tour he moved to Chicago and recorded for Okeh with the stride pianist James P. Johnson.

The Depression ended the recording boom. Johnson worked in a steel mill in Peoria, Illinois, and in 1932 moved to Cleveland, where he lived for the rest of the decade, played on radio and sometimes with the band behind the singer Putney Dandridge. By the late 1930s he was back in Chicago recording for Decca with Roosevelt Sykes and Blind John Davis, among others. In 1939, at a Bluebird session with the pianist Joshua Altheimer, he played an electric guitar for the first time, and over the next five years he cut 34 sides for Bluebird, including "He's a Jelly Roll Baker" and "In Love Again." After the war he moved toward rhythm and blues at King Records in Cincinnati. "Tomorrow Night," a ballad written by Sam Coslow and Will Grosz and recorded with piano and background singers, topped the Billboard race records chart for seven weeks in 1948, reached number 19 on the pop chart and sold three million copies. "Pleasing You," "So Tired" and "Confused" followed as R&B hits.

He toured England in 1952, where the young musician Tony Donegan, on the same bill, took the stage name Lonnie Donegan in his honor, and then settled in Philadelphia and worked in a steel foundry and as a janitor. In 1959 the disc jockey Chris Albertson found him working at the Benjamin Franklin Hotel and produced Blues by Lonnie Johnson for the Bluesville label in 1960, with the tenor saxophonist Hal Singer, the pianist Claude Hopkins, the bassist Wendell Marshall and the drummer Bobby Donaldson. More Prestige sessions followed, among them Blues & Ballads with the banjoist and guitarist Elmer Snowden, who had helped Albertson locate him, and Idle Hours (1961) with Victoria Spivey. A Chicago engagement at the Playboy Club followed, and he guested with Ellington at a folk concert. In 1963 he toured Europe with the American Folk Blues Festival and recorded an album with Otis Spann in Denmark.

In May 1965 he played a Toronto club to an audience of four, and a few weeks later a larger crowd at another club encouraged him to move there. He opened his own club, Home of the Blues, on Yorkville Avenue in 1966; it failed, and he was let go by the man who became its owner. He kept recording and touring in Canada through the rest of the decade. In March 1969 he was hit by a car while walking in Toronto and suffered a broken hip and kidney injuries from which he never fully recovered. After a benefit concert on May 4, 1969, he made a last stage appearance at Massey Hall on February 23, 1970, walking with a cane and singing a couple of songs with Buddy Guy, and he received a standing ovation. He passed away on June 16, 1970. A funeral was held at Mount Hope Cemetery in Toronto, but his family had his body moved to Philadelphia for burial. A nonprofit that places headstones on unmarked blues graves bought one for him around 2014. Smithsonian Folkways issued The Complete Folkways Recordings in 1993.

Johnson is a blues and rhythm and blues figure first: most of his records are vocal blues and ballads, and that is the career that gave him a chart-topping record and a 1960s revival. His jazz importance rests on a narrower body of work from 1927 to 1930, when he played single-note, pick-played guitar solos with string bends and vibrato, often on twelve-string guitar, and brought them to Armstrong's and Ellington's records and to the Eddie Lang duets. The blues historian Gerard Herzhaft called him the creator of the note-by-note guitar solo that became standard in jazz, blues, country and rock, and writers have listed Django Reinhardt, T-Bone Walker and virtually every later electric blues guitarist among those who learned from him; Charlie Christian's profile notes that Christian drew more from horn players than from guitarists like Lang or Johnson. B.B. King cited Johnson as a formative influence, and in his autobiography he said Johnson and Blind Lemon Jefferson hit him hardest as a boy because their voices sounded so natural and believable. Bob Dylan, who met him in New York, said he learned from watching him, and Robert Johnson's "Malted Milk" is often heard as a reworking of Lonnie Johnson songs. The writer Elijah Wald points out that in the 1920s and 1930s Johnson was known mainly as a sophisticated, urbane singer rather than as a guitarist: none of the forty ads for his records that ran in the Chicago Defender between 1926 and 1931 mentioned the guitar. His lyrics treated the social conditions of urban Black life ("Racketeers' Blues," "Hard Times Ain't Gone Nowhere," "Fine Booze and Heavy Dues") and the nuances of love between men and women without Tin Pan Alley sentiment. Elvis Presley's early version of "Tomorrow Night" borrowed his phrasing, and Jerry Lee Lewis recorded the song in 1957.