John Paul Pizzarelli Jr. was born on April 6, 1960, in Paterson, New Jersey, the son of the swing guitarist Bucky Pizzarelli and Ruth Pizzarelli. His younger brother Martin became a bassist and later his trio partner. He took up guitar as a child, picked up some banjo from his great-uncles Pete and Bobby Domenick, and played trumpet through his college years at the University of Tampa and William Paterson University. He was largely self-taught on guitar and has called his father his most important teacher, from 1980 to 1990. As a teenager he sat in with Benny Goodman, Les Paul, Zoot Sims, the bassist Slam Stewart and Clark Terry, and his first professional jazz job, in February 1980 at New York University's Loeb Student Center, was alongside Sims and his father. That year he also made the duo album 2 X 7 = Pizzarelli with Bucky for Stash, a set of seven-string guitar duets. The seven-string guitar, whose extra low string lets him play bass lines under his own solos, has been his signature instrument ever since.

His own debut, I'm Hip (Please Don't Tell My Father), came out on Stash in 1983 with Bucky Pizzarelli on guitar, followed by Hit That Jive, Jack! (1985) and Sing! Sing! Sing! (1987). My Blue Heaven appeared on Chesky in 1990, and in 1992 he began recording for Novus/RCA, where All of Me (1992, with a studio big band and strings), Naturally (1993), New Standards (1994), and After Hours (1996) built his audience. He formed the John Pizzarelli Trio in 1993 with the pianist Ray Kennedy and Martin on bass, after earlier trio work with the pianist Ken Levinsky. That summer the trio opened for Frank Sinatra on tours of the United States and Europe, and he later took part in Sinatra's 80th birthday celebration. Between 1992 and 2000 he also worked repeatedly with the singer Rosemary Clooney, playing guitar on Do You Miss New York? (1993) and again on her bossa nova album Brazil (2000), where he also sings on several tracks. Dear Mr. Cole (1994), a tribute to Nat King Cole with the pianist Benny Green and the bassist Christian McBride, set the pattern for the songbook and tribute albums that define his catalog. In 1997 he starred in the Broadway revue Dream, built around the songs of Johnny Mercer, and the same year Our Love Is Here to Stay (RCA) reached the Billboard Top Ten of the traditional jazz chart. Meets the Beatles followed in 1998 and a second Cole album, P.S. Mr. Cole, in 1999.

From 2000 he recorded for Telarc: Kisses in the Rain and Let There Be Love (both 2000), the concert album Live at Foxwoods Resort Casino (2002), and The Rare Delight of You (2002), a collaboration with the pianist George Shearing. Live at Birdland, recorded over four nights in September 2002 and released in 2003, marked ten years of the trio. Bossa Nova (2004), largely Brazilian songs by Antonio Carlos Jobim, was a departure from the American songbook, and Knowing You (2005) returned to it, with a title track he wrote himself. Dear Mr. Sinatra (2006) was recorded with the Clayton-Hamilton Jazz Orchestra, With a Song in My Heart (2008) took on the music of Richard Rodgers, and Rockin' in Rhythm (2010) saluted Duke Ellington with arrangements by Don Sebesky. Double Exposure (2012) mixed standards with pop songs from his youth. Alongside his own dates he recorded with his father and brother on Generations (Arbors, 2007) and Family Fugue (2011), and he played guitar on James Taylor's October Road (2002) and his Christmas albums, and on Paul McCartney's standards album Kisses on the Bottom (2012).

Midnight McCartney (Concord, 2015) turned McCartney's songs into trio and orchestral jazz, with Sebesky orchestrating and his wife, Jessica Molaskey, co-producing. Sinatra & Jobim @ 50 (2017) marked half a century since the 1967 Sinatra and Jobim sessions, with Jobim's grandson Daniel Jobim singing and playing piano, and For Centennial Reasons: 100 Year Salute to Nat King Cole (2019) returned to Cole for his centenary with the bassist Mike Karn. Bucky Pizzarelli died on April 1, 2020, at 94, from complications of COVID-19, and John's mother, Ruth, passed away a week later. John co-produced James Taylor's American Standard (2020), which won the Grammy for Best Traditional Pop Vocal Album, and recorded Better Days Ahead: Solo Guitar Takes on Pat Metheny (2021), a solo-guitar album of music by Pat Metheny dedicated to his parents. His trio with Karn and the pianist Isaiah J. Thompson recorded Stage & Screen (Palmetto, 2023), made up of show and film songs. Dear Mr. Bennett, a tribute to Tony Bennett, was released on Green Hill Music on March 3, 2026, ahead of the singer's August 3 centenary, and a five-song follow-up EP, P.S. Mr. Bennett, came out in August.

With Molaskey, a Broadway actress and singer, he co-hosts the weekly radio program Radio Deluxe with John Pizzarelli, which the two record in their Manhattan apartment or their upstate New York cabin and which airs on radio stations across the United States and Canada. The couple have also been regular performers at the Café Carlyle in New York, and he produced several of her albums, including A Good Day (2003) and A Kiss to Build a Dream On (2008). Their daughter, Madeleine Pizzarelli, is a singer, songwriter and guitarist.

Pizzarelli is a swing-rooted singer-guitarist who sings in a light, conversational voice and plays hollow-body jazz guitar, usually a seven-string, so that he can state a bass line, chords and a melody in a single passage. He has named Nat King Cole as the inspiration for his career, and his guitar, piano and bass trio format follows Cole's. Les Paul and Django Reinhardt were among his early guitar heroes, and his tastes stretched from rockabilly to singer-songwriter folk, which helps explain the Paul McCartney, Beatles and Metheny projects next to the Cole, Sinatra, Ellington, Mercer and Rodgers tributes. He arranges for his own groups and keeps a relaxed, humorous stage manner; AllMusic calls him an ebullient performer with a soft voice and a knack for swinging, old-school jazz. His father was his model for tone and time on the guitar, and the two made records together for more than three decades.