Joseph DeFrancesco was born on April 10, 1971, in Springfield, Pennsylvania, a Philadelphia suburb in Delaware County, into three generations of working musicians. His grandfather and namesake played saxophone and clarinet, his father, "Papa" John DeFrancesco, was a Philadelphia-area Hammond organist, and his older brother, Johnny, became a blues guitarist. He was four when he started on his father's B-3, and he was sitting in on his father's gigs by five or six, learning records by Jimmy Smith, the organist he later called his idol. He studied at the Settlement Music School in Philadelphia, and at ten played his first paid gig, at Gert's Cocktail Lounge on South Street, where a Monday-night jam session drew regulars such as the tenor saxophonist Hank Mobley and the drummer Philly Joe Jones. As a boy he also sat in with veterans such as Jack McDuff, and he learned from Philadelphia organists including Trudy Pitts and Shirley Scott.

At the Philadelphia High School for the Creative and Performing Arts his classmates included Christian McBride, Kurt Rosenwinkel and the drummer Ahmir "Questlove" Thompson. He won the Philadelphia Jazz Society's McCoy Tyner Scholarship and was a finalist in the first Thelonious Monk International Jazz Piano Competition, where Columbia Records executive George Butler heard him; Columbia gave him an exclusive recording contract at sixteen. Before his own debut he recorded with Grover Washington Jr. on Strawberry Moon (1987) and played keyboards on Miles Davis's Amandla (1989). Davis had met him on a local Philadelphia television program and invited him on tour after he finished high school in 1988; inspired by Davis, DeFrancesco took up the trumpet, which he played from then on alongside the organ.

His debut, All of Me (1989), began five Columbia albums in five years: Where Were You? (1990), Part III (1991), Reboppin' (1992) and Live at the 5 Spot (1993), with guests including Houston Person, Illinois Jacquet, John Scofield, Kirk Whalum and Jack McDuff. He toured with his own quartet from about the age of eighteen. After Columbia he recorded for Muse and Big Mo, led an organ trio with the guitarist Paul Bollenback and the drummer Byron Landham, and joined John McLaughlin and Dennis Chambers in the Free Spirits, which recorded Tokyo Live at the Blue Note in Tokyo in December 1993 (DeFrancesco also played trumpet on it). Elvin Jones replaced Chambers on McLaughlin's After the Rain (1995), and the McLaughlin association brought DeFrancesco his largest international audience.

From 1998 he recorded for HighNote and, beginning with Joey DeFrancesco's Goodfellas (1999), for Concord. He made Incredible! (2000) with Jimmy Smith as a guest, and Legacy (2005), which was Smith's last recording; Smith passed away that year. His HighNote catalog is full of tributes: The Champ to Smith, The Philadelphia Connection to Don Patterson, Plays Sinatra His Way, Finger Poppin' to Horace Silver and Never Can Say Goodbye (2010) to Michael Jackson, which earned a Grammy nomination. He also sang, most prominently on the big-band album Singin' and Swingin' (2001), and in the 2009 film Moonlight Serenade played a character named Frank D and is credited as composer and producer. Between 2011 and 2015 he released 40, Wonderful! Wonderful! with Larry Coryell and Jimmy Cobb, One for Rudy and Trip Mode, and in 2014 joined Bobby Hutcherson and David Sanborn on Enjoy the View, with Billy Hart on drums.

In his last years he led a quartet billed as Joey DeFrancesco and the People (Project Freedom, Mack Avenue, 2017) and made two albums with Van Morrison, You're Driving Me Crazy and The Prophet Speaks, both in 2018. That November he began playing tenor saxophone. In the Key of the Universe (2019) added Pharoah Sanders to his group and was nominated for a Grammy, and on More Music (2021) he played organ, piano and other keyboards, trumpet and tenor saxophone, and sang. He was prominently featured on Christian McBride's Grammy-winning For Jimmy, Wes and Oliver (2020) and hosted a weekly organ program, Organized, on SiriusXM's Real Jazz channel.

His final recording session took place on August 16, 2022, and his last live engagement was a weekend stand at Keystone Korner in Baltimore, August 12 to 14. He passed away on August 25, 2022, at age 51, of a heart attack; his wife and manager, Gloria DeFrancesco, announced his death. He had won the DownBeat Critics Poll for organ nine times, won the magazine's Readers Poll every year from 2005 until his death, and in 2013 was in the first class inducted into the Hammond Hall of Fame. A posthumous album recorded at those Baltimore shows, Live at Keystone Korner, with guitarist Lucas Brown and drummer Anwar Marshall, was issued on Mack Avenue on October 16, 2026.

DeFrancesco's playing joined the strands of Philadelphia organ jazz he grew up inside: the blues-rooted soul jazz of Jimmy Smith, Jack McDuff and Shirley Scott, the hard bop of the city's club circuit, and the modal language of Larry Young, which NPR also set beside the harmony of pianists such as McCoy Tyner. He was a virtuoso of the instrument's full console, with fast right-hand lines, bass lines in the left hand and the pedals, and quick changes of registration, and critics prized his rhythmic pocket as much as his speed. In his 2011 autobiography Pat Martino described him as an exceptional artist and a ferocious player in the tradition of Smith and the Philadelphia organists, and Christian McBride said that DeFrancesco had nothing left to prove on organ, which is why he took up trumpet and saxophone. His trumpet playing grew out of his admiration for Miles Davis, and his tenor saxophone, begun in 2018, was featured on More Music. In his last years he spoke of a "spiritual jazz" direction that took in Pharoah Sanders and Sun Ra. He was also involved in designing and endorsing digital keyboards and organs, and the 1989 debut that made him a teenage star is widely credited with helping bring the Hammond B-3 back into jazz.