James Fletcher Henderson was born in Cuthbert, Georgia, in 1897. He grew up in a middle-class African-American family. His father, Fletcher H. Henderson Sr. (1857–1943), was the principal of the nearby Howard Normal Randolph School from 1880 until 1942. His home, now known as the Fletcher Henderson House, is a historic site. His mother, a teacher, taught him and his brother Horace to play the piano. He began lessons by the age of six. His father would occasionally lock Fletcher in his room to practice for hours. By age 13, Henderson possessed a keen ability to read music and sense pitch. He pursued the studies with his mother and further engaged himself in lessons on European art. Although a talented musician, Fletcher Henderson decided to dedicate himself to math and science. At age 18 he moved to Atlanta, Georgia, and changed his name to Fletcher Henderson, giving up James, his grandfather’s name. He attended Atlanta University (where he was a member of the fraternity Alpha Phi Alpha) and graduated in 1920 with a bachelor’s degree in chemistry and mathematics. After graduation, he moved to New York City to attend Columbia University for a master’s degree in chemistry. Finding his job prospects in chemistry to be poor because of his race, Fletcher turned to music. After arriving in New York City, Fletcher Henderson shared an apartment with a pianist who worked as a musician. When his roommate was too sick to perform, Henderson took his place in the Riverboat Orchestra, which soon gave him a job as a full-time replacement, helping him land a job with Black Swan Records in 1921–1923. During the 1920s, he played piano accompaniment for blues singers. He also led the backing group for Ethel Waters during one of her national tours.

Before 1923, Fletcher Henderson’s group was more of a dance band than a jazz band, though its music was inflected with the ragtime rhythms that had been popular for some time. In 1922 he formed his own band, which was resident first at Club Alabam, then at the Roseland Ballroom, and it quickly became known as the best African-American band in New York. In the 1920s, he did not do very many band arrangements. By late 1923 and into 1924, the arrangements by Don Redman were featuring more solo work, but when Louis Armstrong joined his orchestra in 1924, Henderson realized the potential for richer orchestration. Although Armstong played in the band for only a year, he influenced its members, as they began to imitate his style. Henderson’s band boasted the formidable arranging talents of Don Redman from 1922 to 1927. After Redman’s departure from the band in 1927, Henderson took on some of the arranging, but Benny Carter was Redman’s replacement as saxophone player and arranger from 1930–31, and Henderson also bought scores from freelance musicians (including John Nesbitt from McKinney’s Cotton Pickers). Fletcher Henderson developed his arranging skills from 1931 to the mid-1930s. His band c. 1925 included Howard Scott, Coleman Hawkins (who started with Henderson in 1923, playing the tuba parts on a bass saxophone, and quickly moving to tenor saxophone and a leading solo role), Louis Armstrong, Charlie Dixon, Kaiser Marshall, Buster Bailey, Elmer Chambers, Charlie Green, Ralph Escudero, and Don Redman.

In 1925, with Henry Troy, he wrote “Gin House Blues”, recorded by Bessie Smith and Nina Simone among others. His other compositions include “Soft Winds”. Fletcher Henderson recorded extensively in the 1920s for nearly every label, including Vocalion, Paramount, Columbia, Olympic, Ajax, Pathé, Perfect, Edison, Emerson, Brunswick, and the dime-store labels Banner, Oriole, Regal, Cameo, and Romeo. From 1925–1930, he recorded primarily for Columbia and Brunswick/Vocalion under his own name and a series of acoustic recordings as the Dixie Stompers for Harmony Records and associated dime-store labels (Diva and Velvet Tone). During the 1930s, he recorded for Columbia, Crown (as “Connie’s Inn Orchestra”), ARC (Melotone, Perfect, Oriole, Vocalion), as well as Victor, and Decca. Starting in the early 1920s, he recorded popular hits and jazz tunes. In 1924 he and his band recorded 80 sides. His version of the pop tune “I Can’t Get the One I Want”, recorded about June 19, 1924, was issued on at least 23 labels. In addition to Armstrong, lead trumpeters included Henry “Red” Allen, Joe Smith, Rex Stewart, Tommy Ladnier, Doc Cheatham and Roy Eldridge. Lead saxophonists included Coleman Hawkins, Buster Bailey, Benny Carter and Chu Berry. Sun Ra also worked as an arranger during the 1940s, during Henderson’s engagement at the Club DeLisa in Chicago. Sun Ra said that on first hearing Henderson’s orchestra as a teenager he assumed that they were angels because no human could produce such beautiful music.

Although Fletcher Henderson’s band was popular, he had little success in managing it. His lack of recognition outside of Harlem had to do more with the times in which he lived, apparently lackluster management, and the hard times that resulted after the 1929 stock market crash. Fletcher had a knack for finding talent, but he did not have much luck keeping it. On many occasions he lost talented members to other bandleaders. He also had trouble with finances. When the band split up in 1934, he was forced to sell some of his popular arrangements to Benny Goodman to keep them together. After about 1931, his own arrangements became influential. In addition to arrangements for his band, he wrote arrangements for Teddy Hill, Isham Jones and Benny Goodman. He injured his shoulder in an auto accident in 1928. His wife, Leora, blamed the accident for his diminishing success. She said that John Hammond and Benny Goodman bought Henderson’s arrangements to support him, that Goodman always gave Henderson credit for the arrangements and said that he played them better than his own. In addition, Goodman and Hammond organized broadcasts and recordings to help Henderson when he was ill.