Cassandra Wilson was born Cassandra Fowlkes on December 4, 1955, in Jackson, Mississippi, the youngest of three children of Herman Fowlkes Jr., a guitarist, bassist and music teacher, and Mary McDaniel, an elementary-school teacher. She studied piano from age six to thirteen and played clarinet in her school's concert and marching bands. When she lost patience with formal lessons she asked her father to teach her guitar; he pointed her to a Mel Bay method book instead, and she worked out an intuitive approach on her own while writing folk-style songs. She also sang in school musicals, including a turn as Dorothy in The Wizard of Oz. She attended Millsaps College and Jackson State University, graduating from Jackson State with a degree in mass communications, and spent her nights singing in R&B, funk and pop cover bands and in local coffeehouses. The Black Arts Music Society, founded by John Reese and Alvin Fielder, gave her her first chances to perform bebop.

In 1981 she moved to New Orleans to work as an assistant public affairs director at the television station WDSU, and she sang on the first album by a local Latin band, Jasmine, produced by Allen Toussaint at his Sea-Saint studio. The elder musicians Earl Turbinton, Alvin Batiste and Ellis Marsalis encouraged her to take jazz seriously, and in 1982 she moved to New York City. There she studied ear training with the trombonist Grachan Moncur III, frequented jam sessions under the pianist Sadik Hakim, a Charlie Parker alumnus, and met the alto saxophonist Steve Coleman, who urged her to write her own material instead of leaning on the standard repertoire. She became the vocalist and one of the founding members of Coleman's M-Base collective, which recast funk and soul rhythms inside jazz structures, and she sang on Coleman's Motherland Pulse (1985), on several Five Elements albums including On the Edge of Tomorrow, World Expansion and Sine Die, and on the M-Base Collective's large-ensemble album Anatomy of a Groove (1992). She also toured with the trio New Air, led by Henry Threadgill, and sang three selections on its album Air Show No. 1, recorded in Milan in June 1986.

Her first records under her own name were a trio date of standards, Newyorker in a Sentimental Mood, recorded in Japan in 1985 for JAL Strato Sound, and Point of View, recorded in Brooklyn in December 1985 and issued by the Munich label JMT in 1986. JMT put out most of her work for the rest of the decade, mostly her own songs in an M-Base setting, with outside writing from Coleman, Jean-Paul Bourelly and James Weidman. The exception, Blue Skies (1988), was an album of standards with the pianist Mulgrew Miller, the bassist Lonnie Plaxico and the drummer Terri Lyne Carrington, and it brought her first wide critical praise. Jumpworld (1990), She Who Weeps (1991), on which her father, Herman Fowlkes, played electric bass on one track, Live (1991) and After the Beginning Again (1992) followed, and in 1989 she opened for Miles Davis at the JVC Jazz Festival in Chicago.

Signing with Blue Note in 1993 changed her audience. Blue Light 'til Dawn, produced by Craig Street with mostly acoustic arrangements, mixed her own songs with material by Robert Johnson, Joni Mitchell, Van Morrison and Ann Peebles; it had sold more than 250,000 copies by March 1996, and her father died while it was being made. From then on her repertoire moved freely among blues, country, folk, pop and world music, taking in Johnson's "Come On in My Kitchen," Mitchell's "Black Crow," the Monkees' "Last Train to Clarksville" and Hank Williams's "I'm So Lonesome I Could Cry." New Moon Daughter (1996) reached number one on Billboard's jazz albums chart and won the Grammy Award for Best Jazz Vocal Performance at the 1997 ceremony. She sang the role of Leona in Wynton Marsalis's oratorio Blood on the Fields, which won the 1997 Pulitzer Prize for Music, and in 1997 she recorded the duo album Rendezvous with the pianist Jacky Terrasson. She produced Traveling Miles (1999), a tribute to Miles Davis that grew out of concerts at Lincoln Center in November 1997 and put new lyrics to Davis themes.

Belly of the Sun (2002) was partly recorded in a Clarksdale, Mississippi, train station, and the guitarist Fabrizio Sotti co-produced Glamoured (2003) and Another Country (2012), a voice-and-guitar set recorded in Florence and New Orleans that ended her twenty years with Blue Note and came out on eOne. Thunderbird (2006) was produced by T Bone Burnett and Keefus Ciancia, and Loverly (2008), recorded in a rented house in Jackson with the pianist Jason Moran, won the Grammy for Best Jazz Vocal Album at the 2009 ceremony. Silver Pony (2010) combined live tracks from European tour dates with studio work, and her final studio album, Coming Forth by Day (2015, Legacy), marked the centenary of Billie Holiday's birth. In 2015 she also gave a concert at the Apollo Theater for that anniversary. DownBeat named her female jazz vocalist of the year from 1994 to 1996, and she received the Miles Davis Prize at the Montreal International Jazz Festival in 1999. Time called her "America's Best Singer" in 2001, and in 2022 she was named an NEA Jazz Master in a class that also included Billy Hart, Stanley Clarke and Donald Harrison. A marker for her was added to the Mississippi Blues Trail in 2010, and she received honorary doctorates from The New School (2015) and Berklee College of Music (2020).

She had a son, Jeris, born in the late 1980s, and was married to the actor Isaach de Bankolé from 2000 to 2003; he directed the concert film Traveling Miles: Cassandra Wilson (2000). Cassandra Wilson died at home in Jackson, Mississippi, at 70. Her manager, Robert Torre, announced her death in a statement to the radio station WBGO that gave the date as Wednesday, September 2, 2026, the date used here; the Hinds County coroner, as reported by the Associated Press, placed it on the Tuesday morning before. No cause of death was given, and her family asked for privacy.

Wilson sang in a smoky, low-lying contralto that the critic Gary Giddins described as having an "unmistakable timbre and attack." She stretched and bent pitches, drew out syllables and moved her tone from dusky to hollow, and AllMusic's Thom Jurek compared the originality of her phrasing to that of a horn player or pianist. She was heavily influenced by the singers Abbey Lincoln and Betty Carter, the M-Base years with Steve Coleman taught her to start from rhythm and build songs outward, and Miles Davis was among her greatest influences. From Blue Light 'til Dawn onward she rebuilt blues, folk, pop and country songs as small, mostly acoustic ensemble pieces, often with Brandon Ross, Kevin Breit or Marvin Sewell on guitar, and she played guitar herself on records including New Moon Daughter, Traveling Miles, Glamoured, Thunderbird and Coming Forth by Day. Giddins wrote in 2008 that the two Craig Street albums uncovered her Mississippi roots and made her a natural blues singer in the Delta tradition. Critics were more divided about the later, producer-driven records: reviewers of Thunderbird (2006), for example, described a move away from jazz toward a contemporary roots sound. The pianist Jon Batiste, who played in her band on Silver Pony and toured with her, said after her death that her phrasing and her weaving of folkloric, R&B and diasporic music with experimental and popular genres had a major impact on him.