He made his first recordings in Memphis for Sun Records, under the direction of Sam Phillips. In 1955, he was recruited by Muddy Waters to come to Chicago and join his band. Cotton became Muddy's bandleader and stayed with the group until 1965. In 1965, he formed the Jimmy Cotton Blues Quartet, with Otis Spann on piano, to record between gigs with the Muddy Waters band. He eventually left to form his own full-time touring group. His first full album, on Verve Records, was produced by the guitarist Mike Bloomfield and the singer and songwriter Nick Gravenites, who later were members of the band Electric Flag.
In the 1970s, Cotton played harmonica on Muddy Waters' Grammy Award–winning 1977 album Hard Again, produced by Johnny Winter.
In 1965 he formed the Jimmy Cotton Blues Quartet, with Otis Spann on piano, to record between gigs with Waters's band. Their performances were captured by producer Samuel Charters on volume two of the Vanguard recording Chicago/The Blues/Today! After leaving Waters's band in 1966, Cotton toured with Janis Joplin while pursuing a solo career. He formed the James Cotton Blues Band in 1967. The band mainly performed its own arrangements of popular blues and R&B from the 1950s and 1960s. Cotton's band included a horn section, like that of Bobby Bland's. After Bland's death, his son told news media that Bland had recently discovered that Cotton was his half-brother.
Cotton appeared on the cover of the July–August 1987 issue of Living Blues magazine (number 76). He was featured in the same publication's 40th anniversary issue of August–September 2010.
In 2006, Cotton was inducted into the Blues Hall of Fame at a ceremony conducted by the Blues Foundation in Memphis. He has won or shared ten Blues Music Awards.
Cotton battled throat cancer in the mid-1990s, but he continued to tour, using singers or members of his backing band as vocalists. On March 10, 2008, he and Ben Harper performed at the induction of Little Walter into the Rock and Roll Hall of Fame, playing "Juke" and "My Babe" together; the induction ceremony was broadcast nationwide on VH1 Classic. On August 30, 2010, Cotton was the special guest on Larry Monroe's farewell broadcast of Blue Monday, which he had hosted on radio station KUT in Austin, Texas, for nearly 30 years.
Cotton died of pneumonia on March 16, 2017, at the age of 81, at a medical center in Austin, Texas, and was buried on July 11, 2017, in Texas State Cemetery in Austin.
