Alphonse Lee Mouzon was born in Charleston, South Carolina, on November 21, 1948. He got serious about drums at Bonds-Wilson High School, where he studied with a saxophonist and a drummer, and after graduating he moved to New York City. He studied drama and music at the City College of New York and medicine at Manhattan Medical School, and took drum lessons from Bobby Thomas, the drummer in Billy Taylor's trio. In 1968 he played percussion in the Broadway production of Promises, Promises, and by the start of the 1970s he was a working session drummer.

The early credits show how fast he moved between worlds. He was the original drummer of Weather Report: the band's debut album for Columbia, released on May 12, 1971, credits him with drums and voice alongside Joe Zawinul, Wayne Shorter, Miroslav Vitouš and Airto Moreira, and Eric Gravatt took the drum chair later that year. He also played on Tim Hardin's Bird on a Wire (Columbia, 1971), on Gil Evans's 1971 album Gil Evans, and on Wayne Shorter's Odyssey of Iska (Blue Note, 1971), where he shared the drum chair with Billy Hart. In January 1972 he recorded Sahara with McCoy Tyner, the pianist's first album for Milestone, in a quartet with Sonny Fortune and Calvin Hill; on the title piece Mouzon also plays trumpet and reeds as well as percussion.

His own recording career began at Blue Note. The Essence of Mystery was recorded at A&R Studios in New York on December 13 to 15, 1972, with Buddy Terry, Sonny Fortune, Larry Willis, Buster Williams and Wilbur Bascomb Jr., and Mouzon himself on drums, timpani, tabla, electric piano, clavinet, Mellotron and vocals. Funky Snakefoot followed after sessions at Electric Lady Studios on December 10 to 12, 1973, with Randy Brecker on trumpet; it put his keyboards and singing ahead of his drumming and sat closer to R&B than almost anything else on the label. Mind Transplant, recorded at Wally Heider Studio III in Los Angeles between December 4 and 10, 1974 and released in 1975, added guitarists Tommy Bolin and Lee Ritenour, Jay Graydon, keyboardist Jerry Peters and bassist Henry Davis under producer Skip Drinkwater, and AllMusic calls it arguably his finest solo release. The Man Incognito (1976), his fourth album, was recorded in Hollywood in December 1975 and January 1976 and built around the groove of "Take Your Troubles Away," with Dave Grusin, George Duke and David Benoit among the players.

From 1973 to 1975 he was a founding member of guitarist Larry Coryell's Eleventh House, the electric band Coryell assembled in the wake of the Mahavishnu Orchestra. Introducing the Eleventh House (Vanguard, 1974) reached No. 163 on the Billboard 200, and Level One (Arista, 1975) included the bassist John Lee. Mouzon and Coryell recorded a reunion album, Back Together Again (Atlantic, 1977), and the Eleventh House met again in the late 1990s. On November 6, 1976 he played at the Berlin Jazz Days with trombonist Albert Mangelsdorff and Jaco Pastorius, a set released on MPS as Trilogue. MPS also issued his Virtue (1977), recorded in Stuttgart in November 1976 with Gary Bartz on alto and soprano saxophone, and In Search of a Dream (1978). Outside his own dates he played drums on one track of Al Di Meola's debut Land of the Midnight Sun (Columbia, 1976), and in 1979 he joined Kimiko Kasai's Butterfly, recorded with Herbie Hancock and most of the Headhunters.

In the early 1980s he made his most widely heard records for Pausa. Morning Sun (1981), with Herbie Hancock, Lee Ritenour, Michael Brecker and Hubert Laws among its guests, became his biggest seller in Southeast Asia, especially the Philippines, where its songs stayed on radio and in commercials for decades. By All Means (1981) featured Herbie Hancock, Lee Ritenour, Freddie Hubbard and the Seawind Horns. In 1992 he founded his own label, Tenacious Records, and released The Survivor on it, later reissuing much of his catalog there and adding new albums through Angel Face (2011). He toured Europe and the United States for years with his own trio, quartet or quintet, and in 1995 Jazziz readers voted him the second best multi-instrumentalist.

Acting ran alongside the music. He composed "The Blue Spot" for the jazz club scene in That Thing You Do! (1996), directed by Tom Hanks, and appeared in the film as an actor and drummer, and he later appeared in First Daughter and The Dukes and played Miles in the festival film The Highlife (2003). He is credited on drums and percussion on Dingo (1991), the soundtrack album by Miles Davis and Michel Legrand, alongside Harvey Mason among several drummers. In 1995 Robert Plant named Mouzon among the American influences on Led Zeppelin in his Rock and Roll Hall of Fame induction speech.

Mouzon was diagnosed with neuroendocrine carcinoma on September 7, 2016. He passed away at his home in Granada Hills, Los Angeles, on December 25, 2016, at the age of 68, from cardiac arrest according to his son Jean-Pierre Mouzon.

Mouzon belongs to the first wave of jazz-rock drummers, and his reputation sits beside that of Billy Cobham: AllMusic's biographer notes that Cobham gets most of the credit for putting fusion drumming on the map, and that Mind Transplant would have drawn more attention had it not arrived so soon after Cobham's Spectrum (1973). His drumming is powerful and busy, suited to the electric bands of Weather Report and the Eleventh House, but the same hands could keep a straight-ahead quartet moving, as the Sahara date with McCoy Tyner shows.

What separates him from most drummer-leaders is how often he put his other instruments first. On his Blue Note records he sings, and plays keyboards, synthesizers and organ, and Funky Snakefoot, The Man Incognito and many of the later albums are as much funk and R&B as they are jazz. That is the reason he sits with the crossover artists: the jazz side is the Weather Report and Coryell years, the Sahara and Odyssey of Iska sessions and the MPS dates, and the R&B side is the singing and songwriting on his own labels.