Fred Wesley was born on July 4, 1943, in Columbus, Georgia, and grew up in Mobile, Alabama. His father, Fred Wesley Sr., was a high school teacher and big band leader who chaired the music department at Mobile's Central High School, and his grandmother taught piano. He started on piano, moved to trumpet, and played baritone horn and trombone at school. Around the age of twelve his father brought a trombone home, and he switched to it for good. He made his professional debut at twelve in a big band led by his school's music teacher, E.B. Coleman, and soon was sitting in with local R&B acts. He studied music at Alabama State University, played briefly with the Ike & Tina Turner Revue and with Hank Ballard & the Midnighters, and served in the U.S. Army as a bandsman until his discharge in 1967.

When he came out of the Army he formed a group called the Mastersound, which mixed R&B with hard bop and lasted less than a year. The trumpeter Waymon Reed then phoned to say that James Brown needed a trombonist, and Wesley took the job. He was on Brown's records by 1968, including "Say It Loud - I'm Black and I'm Proud" and "Mother Popcorn," left in 1969 after repeated clashes with Brown, and returned in 1971 as musical director and arranger, running the J.B.'s. It was the busiest stretch of his career. "Pass the Peas" (1972) reached No. 29 on the R&B chart, and he co-wrote "Hot Pants." "Doing It to Death" was credited to Fred Wesley & the J.B.'s, reached No. 1 on the soul singles chart and No. 22 on the Hot 100, and was certified gold by the RIAA in July 1973. Brown wrote the song and sang on it, but its title came from a phrase Wesley used. Under his own name he fronted the J.B.'s on Damn Right I Am Somebody and Breakin' Bread (both 1974), and AllMusic singles out his contributions to Brown's Black Caesar, Slaughter's Big Rip-Off and The Payback. He left Brown for good in 1975, together with the saxophonist Maceo Parker.

He joined George Clinton's Parliament-Funkadelic in time for Mothership Connection (1975) and led the Horny Horns, the horn section that worked on Clinton's and Bootsy Collins's records and made two Atlantic albums of its own, A Blow for Me, a Toot to You (1977) and Say Blow by Blow Backwards (1979), with Parker and the trumpeters Rick Gardner and Richard "Kush" Griffith. In the same years he was working in New York as a trombonist for the producer Creed Taylor, on the CTI and Kudu records of the mid-1970s: Hank Crawford's I Hear a Symphony (1975) and Hank Crawford's Back (1976), where he is also credited as a soloist, Esther Phillips's For All We Know (1976), Idris Muhammad's House of the Rising Sun (1976) and George Benson's Good King Bad (1976).

In 1978 he took Al Grey's trombone chair in the Count Basie Orchestra, a job he had wanted since boyhood, because his father's band played Basie's arrangements. He is credited on both volumes of Milt Jackson + Count Basie + The Big Band (Pablo, 1978) alongside the vibraphonist Milt Jackson. He left the band in 1979 because the pay was lower than he had been earning with Clinton. The early 1980s were mostly studio work in Los Angeles, including sessions for Earth, Wind & Fire, the Gap Band and Barry White and arrangements for Curtis Mayfield and Terry Callier, plus House Party (1980), whose title track became his best-known solo single.

He came back to jazz under his own name at the turn of the 1990s. To Someone (Hi Note, 1990), billed to the Fred Wesley Quartet, is a standards date with the pianist Joe Bonner, the bassist Ken Walker and the drummer Bruno Carr. New Friends (Minor Music, 1990) opens with Duke Ellington's "Rockin' in Rhythm" and brings together the pianist Geri Allen, the trombonists Steve Turre and Robin Eubanks, the drummer Bill Stewart, the bassist Anthony Cox, the singer Carmen Lundy and Parker. Comme Ci Comme Ça (1991), Swing & Be Funky (1993) and Amalgamation (1994) followed on Minor Music with the saxophonist Karl Denson as second horn on all three. In the early 1990s he toured as the JB Horns with Parker and the saxophonist Pee Wee Ellis, stayed on as Parker's featured trombonist until 1996, and then formed the Fred Wesley Group, now Fred Wesley and the New JBs. In 1994 he recorded West Coast Boogaloo with the San Diego soul-jazz band the Greyboy Allstars and toured with them in 1995, 1996 and 2012.

His memoir, Hit Me, Fred: Recollections of a Sideman, was published by Duke University Press in September 2002. He was an adjunct professor in the jazz studies department at the University of North Carolina at Greensboro from 2004 to 2006 and has worked as a visiting artist at Berklee College of Music and Columbia College Chicago. After meeting the clarinetist David Krakauer in New York around 2005 he joined him and the rapper and producer Socalled in the funk-klezmer project Abraham Inc., and in 2015 he made Generations with the organist Leonardo Corradi and the drummer Tony Match, a trio that remains his second working band. The same year he was inducted into the Alabama Jazz Hall of Fame. From the Blues and Back (LoEnd Records, September 21, 2023), with the New JBs, was his first studio album in more than a decade. In 2026 the Alabama Humanities Alliance named him an Alabama Humanities Fellow, the state's highest humanities honor, describing him as a Mobile native who lives in Montgomery, and on July 31, 2026 the PRISM Quartet released "Requiem for AJ," a ten-minute piece Wesley composed, with poetry by Ursula Rucker, for the quartet's Generate Music project on the ties between Black and Jewish Americans. He is 83 and still tours with the New JBs and the Generations trio.

Wesley is better known for funk than for jazz, and his career history says so. For most listeners his sound is the slippery, blues-bent trombone on James Brown's and Parliament-Funkadelic's records, set against Maceo Parker's alto, together with the horn arrangements that sit under those songs, and AllMusic notes that his vintage James Brown sides have been sampled endlessly in hip-hop. What makes him a jazz musician as well is the other half of the story: a childhood in a big band household, bebop and the trombone of J.J. Johnson as his listening, a chair in the Count Basie Orchestra in 1978 and 1979, the CTI and Kudu sessions with Creed Taylor, and a run of Minor Music records on which he plays Duke Ellington, "On Green Dolphin Street" and "Autumn Leaves" with working jazz rhythm sections. He has described his own music as a mixture of both, with the Brown material keeping him tied to that legacy and the jazz letting him play the music he loves. As an arranger he did much of the composing and horn writing behind Brown's J.B.'s, and the 2002 memoir is the standard first-person account of how that band worked.