Cyrus Antonio Chestnut was born on January 17, 1963, in Baltimore, the son of McDonald Chestnut, a post-office worker who played piano and organ in church, and Flossie Chestnut, a social-services worker who directed a church choir. His father was his first teacher, and as a boy he played at Mount Calvary Baptist Church. By the age of nine he was studying classical piano at the Peabody Institute while he went on absorbing gospel and jazz at home and in church. He entered the Berklee College of Music in 1981 and graduated in 1985 with a degree in jazz composition and arranging; AllMusic lists a Eubie Blake Fellowship, a Quincy Jones Scholarship and an Oscar Peterson Scholarship among his awards there. In Boston he played in the trombonist Phil Wilson's Rainbow Band, which recorded Latin American Tour in 1985.

After Berklee he became an in-demand sideman for Jon Hendricks, Wynton Marsalis, Terence Blanchard and Donald Harrison. Chestnut was the pianist in the quintet Blanchard and Harrison co-led, and appears on its last Columbia album, Black Pearl (1988); in November 1990 he also played on Harrison's Blakey tribute For Art's Sake, recorded live at Birdland. The association that shaped him most was with Betty Carter, whose working trios were a proving ground for young players; he toured and recorded with her in the early 1990s and is one of the pianists on her It's Not About the Melody (Verve, 1992). She is reported to have urged him to take chances and to surprise her.

His own recording career began in 1992 for the Japanese label Alfa Jazz with The Nutman Speaks and The Nutman Speaks Again, trio dates with the bassist Christian McBride and the drummer Carl Allen, followed by Another Direction in 1993. He then signed with Atlantic, which issued Revelation (1994) with the drummer Clarence Penn, Dark Before the Dawn (1995) and Earth Stories (1996), a mostly original program dedicated to his grandmother that The Washington Post named the year's best jazz instrumental album. He also made a solo hymn album, Blessed Quietness (1996), and was a featured soloist on the soundtrack of Robert Altman's film Kansas City (1996). His self-titled Atlantic album of 1998 brought in James Carter, Joe Lovano, Ron Carter, Billy Higgins, Lewis Nash and the singer Anita Baker. From 1997 he also co-led the Manhattan Trinity with the bassist George Mraz and Nash, a group that recorded for Baybridge and then the Japanese label M&I through 2009, including A Love Story (1999, with the tenor saxophonist Eric Alexander) and a run of standards and songbook albums.

In 2000 he recorded A Charlie Brown Christmas, a reading of Vince Guaraldi's television score with guests including Michael Brecker, Kenny Garrett and Steve Gadd, which reached number three on Billboard's jazz albums chart. Soul Food (2001) closed his Atlantic contract. He moved to Warner Bros. for the trio album You Are My Sunshine (2003) with the bassist Michael Hawkins and the drummer Neal Smith, then to Telarc for Genuine Chestnut (2006), which kept that trio and added the guitarist Russell Malone on some tracks. Later leader albums include Cyrus Plays Elvis (Koch, 2007), the solo Spirit (Jazz Legacy, 2009), Plenty Swing, Plenty Soul (Savant, 2010), co-led with the pianist Eric Reed, and two albums on the drummer Willie Jones III's WJ3 label, The Cyrus Chestnut Quartet (2012) and Soul Brother Cool (2013). Midnight Melodies (Smoke Sessions, 2014) was recorded live at Smoke in New York.

Since 2015 his home label has been HighNote. A Million Colors in Your Mind (2015) used the bassist David Williams and the drummer Victor Lewis. Natural Essence (recorded November 17, 2015, released May 20, 2016) is the album of the trio of Chestnut, Buster Williams on bass and Lenny White on drums, which also performed as Chestnut, Williams & White, including a night at the Oslo Jazzfestival on August 14, 2016. There's a Sweet, Sweet Spirit (2017) added the vibraphonist Steve Nelson, and Kaleidoscope (2018), with the bassist Eric Wheeler and the drummer Chris Beck, reworked pieces by Mozart, Debussy and Satie. His father, McDonald, died in 2021 at 85, and My Father's Hands (2022), with Peter Washington and Nash, is dedicated to him. Rhythm, Melody and Harmony, released on April 25, 2025, is a quartet date with the saxophonist Stacy Dillard, the bassist Gerald Cannon and Beck, built mostly on Chestnut's own compositions.

AllMusic describes a pianist who balances a lithe technique with a soulful style drawn from gospel and a love of swinging hard bop, and the classical side of his training, from the Peabody years, surfaces openly on Kaleidoscope and on the solo hymns of Blessed Quietness. In 2006 Josh Tyrangiel of Time called him the best jazz pianist of his generation, crediting his readiness to leave notes out and play space. Dave Gelly, reviewing My Father's Hands in The Guardian in 2022, likened him to Oscar Peterson at his peak and praised a melodic approach that never seems to be showing off. He has also been a regular accompanist for singers, among them Betty Carter, Jimmy Scott, Madeleine Peyroux and Dee Dee Bridgewater. His own repertoire mixes originals with standards, hymns, pop songs and the music of Elvis Presley and Henry Mancini.