Charles McPherson was born in Joplin, Missouri, on July 24, 1939, and moved to Detroit with his family in 1948, at age nine. In Joplin he had picked at whatever piano he could find and had gone to summer concerts by the territory bands that worked the Midwest and Southwest, where the shape and sound of the saxophone caught his attention before he owned one. He started on flugelhorn and trumpet in his school band at twelve and switched to alto saxophone at thirteen. A classmate pointed him toward Charlie Parker, and hearing "Tico-Tico" from Charlie Parker South of the Border on a candy-store jukebox settled the question of what he wanted to play. By his own account the Detroit street he landed on could hardly have been better chosen: pianist Barry Harris lived five minutes around the corner, trumpeter Lonnie Hillyer lived on the same block, and the Blue Bird Inn was a few doors down, with a house band of Harris on piano, Pepper Adams on baritone saxophone, Paul Chambers or Beans Richardson on bass, and Elvin Jones on drums.

At fifteen McPherson began studying with Harris, whose apartment functioned as an informal conservatory for a generation of Detroit players, and he also took saxophone lessons briefly at the Larry Teal School of Music. Too young to sit in with the older musicians, he and his peers pooled their money to rent a loft with a piano and a drum set, cut seven or eight keys, and played there at two in the morning. That circle included Hillyer, drummers Roy Brooks and Louis Hayes, saxophonist Donald Walden, and the future Motown rhythm-section players James Jamerson and Richard "Pistol" Allen. By nineteen McPherson was working regularly around the city.

He moved to New York in 1959 and, in 1960, joined Charles Mingus, beginning an on-and-off association that ran for roughly twelve years. A 1960 photograph from the original Five Spot Café shows the 21-year-old McPherson standing with Mingus and Pepper Adams. He appears on Mingus (Candid, 1961), on the October 1962 Town Hall concert later issued in full as The Complete Town Hall Concert, on Mingus at Monterey from the September 20, 1964 festival set, on Music Written for Monterey 1965, on the 1972 Columbia studio project Let My Children Hear Music, and on Charles Mingus and Friends in Concert. His last widely documented appearance with the bandleader is Mingus at Carnegie Hall, recorded January 19, 1974. He also took the alto chair on Pepper Adams's 1964 leader date Pepper Adams Plays the Compositions of Charlie Mingus, cut for Motown's Workshop Jazz subsidiary with Thad Jones and Zoot Sims in the band, and worked steadily with Harris outside the Mingus orbit, on Newer Than New (Riverside, 1961) and Bull's Eye! (Prestige, 1968).

McPherson's own recording career started while he was still with Mingus. Bebop Revisited!, cut November 20, 1964 at Rudy Van Gelder's studio with trumpeter Carmell Jones, Harris, bassist Nelson Boyd, and drummer Albert "Tootie" Heath, opened a run of six Prestige albums produced by Don Schlitten: Con Alma! (1965, with Clifford Jordan and Alan Dawson), The Quintet/Live! from the Five Spot with Hillyer and Billy Higgins (1967), From This Moment On! (1968, with Cedar Walton, Pat Martino, and Lenny McBrowne), Horizons (1969), and McPherson's Mood (1970). Three albums for Bob Shad's Mainstream label followed: Charles McPherson (1971), reuniting him with Harris, Hillyer, and Ron Carter; Siku Ya Bibi (Day of the Lady) (1972), a Billie Holiday program with Sam Jones and Leroy Williams and liner notes by Nat Hentoff; and the larger-ensemble Today's Man (1973). Schlitten then brought him to Xanadu for Beautiful! (recorded August 12, 1975, with Duke Jordan), Live in Tokyo (April 14, 1976), New Horizons (recorded September 28, 1977, with Mickey Tucker and Cecil McBee), and Free Bop! (recorded October 23, 1978), the last of these featuring his son, drummer Charles McPherson Jr.

In 1978 McPherson left New York for San Diego, where he still lives, and built a career that combined touring with teaching. He recorded The Prophet for Discovery on April 14, 1983 with pianist Mike Wofford, and Discovery later folded that session together with a July 1989 date as the compilation Follow the Bouncing Ball. In 1988 he was hired for Clint Eastwood's Charlie Parker biopic Bird, supplying the alto voice heard in several scenes and playing the body and fingering that Forest Whitaker's performance was matched to; McPherson has described having to learn to breathe where Parker breathed. The 1990s brought a three-album run for Arabesque: First Flight Out (recorded January 25 and 26, 1994, with Tom Harrell, Michael Weiss, Peter Washington, and Victor Lewis), Come Play With Me (1995, with Mulgrew Miller and Lewis Nash), and Manhattan Nocturne (recorded April 1997). He also led Live at Vartan Jazz, taped in Denver on March 15 and 16, 1996, and recorded the Venus quartet date But Beautiful with Steve Kuhn in July 2003.

McPherson's later work centers on composition. His collaboration with the San Diego Ballet and its artistic director, Javier Velasco, began with Sweet Synergy Suite, funded by a San Diego Foundation Creative Catalyst Fund grant and premiered by the company in February 2015; he was named the company's resident composer in 2016. Song of Songs, eight pieces for jazz quintet and voice drawn from the biblical love poem, had its world premiere on May 24, 2019 at San Diego's Lyceum Theatre, with McPherson's daughter Camille McPherson, a soloist with the company, as featured dancer. He recorded Song of Songs and Sweet Synergy Suite together at Van Gelder Studios on December 9 and 10, 2019 and issued them as Jazz Dance Suites, dedicated to Camille; JazzTimes readers voted it Best New Release and named McPherson Artist of the Year for 2020. Jazz at Lincoln Center marked his eightieth birthday in April 2019 with a program of seven of his compositions arranged for the orchestra. He holds an honorary Doctor of Fine Arts from California State University San Marcos (2015) and received the Don Redman Jazz Heritage Award in 2016, the Detroit Jazz Festival's Robert E. McCabe Guardian of Jazz Award in 2022, a Mellon Foundation and Jazz Foundation of America Jazz Legacies Fellowship in February 2026, and the Jazz Journalists Association's alto saxophonist of the year award in June 2026. His most recent album, Reverence, was recorded live at New York's Smoke Jazz Club from November 1 to 5, 2023 and released on Smoke Sessions on April 26, 2024; its program includes "Blues for Lonnie in Three" and "Ode to Barry," written for Lonnie Hillyer and Barry Harris.

McPherson took Charlie Parker as a starting point and never abandoned him, but he is not a copyist: his lines are longer and more asymmetrical than Parker's, his sound is broader and more vocal in the middle register, and his ballad playing leans toward an operatic projection that writers have consistently singled out. The schooling shows in the harmony. Barry Harris's method, absorbed from age fifteen and reinforced across five decades of playing together, gave McPherson a way of running bebop's chord movement that stays melodic even at speed. The dozen years with Charles Mingus pushed against that discipline in a useful way, forcing him into blues shouting, collective free playing, and abrupt tempo shifts that a strict bebop apprenticeship would not have supplied. Critics have treated him as a rare case of a bebop musician who kept growing inside the idiom rather than leaving it: the Detroit critic Mark Stryker calls him one of the most potent musicians to emerge from that city's mid-century bebop scene, and Stanley Crouch, writing in the New York Times, described him as a singular voice who never sacrificed the fluidity of his melody making. His compositional work for the San Diego Ballet, which sets bebop and Afro-Latin material against choreography, is the clearest evidence that the growth continued into his eighties.