Mike Stern was born Michael Sedgwick in Boston on January 10, 1953, the son of the sculptor and arts patron Helen Phillips Burroughs and Henry Dwight Sedgwick V, and took the surname of his stepfather, Philip M. Stern. He grew up in Washington, D.C., picked up a guitar at twelve and learned it from records by B.B. King, Eric Clapton and Jimi Hendrix rather than from any jazz source. Serious study came later, at the Berklee College of Music in Boston, where he is listed today on the guitar faculty as a member of the class of 1975.

He was twenty-two when Blood, Sweat & Tears hired him, and he stayed roughly three years, appearing on More Than Ever (Columbia, 1976) and Brand New Day (ABC, 1977). The credit lists show how much of that horn-band work was farmed out to New York session players: on More Than Ever Stern is named as the group's electric guitarist, but the tracks are carried by Steve Khan, Eric Gale and Hugh McCracken, and Stern's only individual player credit is the lead guitar on "Heavy Blue." At the same time he was playing in a Washington glam-rock quintet, the Dubonettes, later renamed Charlie and the Pep Boys, which released one album, Daddy's Girl, in 1976. In 1979 he joined Billy Cobham's fusion band and made Stratus, cut direct to disc at CBS Studio 1 in London on March 18, 1981, alongside Michal Urbaniak, Gil Goldstein and Tim Landers.

Miles Davis brought him into the band that ended a five-year retirement, and it changed everything. Stern is the guitarist on "Fat Time," the opening track of The Man with the Horn (1981), a piece Davis titled after the nickname he had given him; Barry Finnerty plays the rest of the album. The live We Want Miles (1982), assembled from Boston, New York and Tokyo dates in 1981, is Stern the whole way through, in a band with Bill Evans on soprano saxophone, Marcus Miller on bass, Al Foster on drums and Mino Cinelu on percussion. By the time of Star People (1983), John Scofield had been brought in and both guitarists are credited without any breakdown of who plays where. Stern left in 1983, toured through 1983 and 1984 with Jaco Pastorius's Word of Mouth band, and returned to Davis for a further spell in 1985. Those were also the years in which he was drinking heavily and using heroin; both he and his wife, the guitarist Leni Stern, later went into rehabilitation, helped by Michael Brecker among others.

His own recording career began quietly and in the wrong hemisphere. Neesh, made for the Japanese Trio/Kenwood label and issued there in 1983, has Stern's compositions and arrangements throughout, with David Sanborn on alto, Hiram Bullock producing and playing second guitar, Tom Barney on bass and Victor Lewis on drums. It is his first album as a leader and it had no Western release, which is why Upside Downside (Atlantic, 1986) is often taken for his debut. That second record announced the working formula he kept for a decade: Bob Berg's tenor against Stern's guitar, a hard-swinging electric rhythm section, and one guest appearance by Pastorius, on the title track. Time in Place followed in 1988, recorded at Skyline Studios in December 1987 with Peter Erskine, Jim Beard, Jeff Andrews and Don Alias, and Jigsaw in 1989, produced by Steve Khan and containing "Chief," his tribute to Davis. In 1989 he put together a touring quartet with Berg, Dennis Chambers and Lincoln Goines that lasted until 1992 and produced Odds or Evens, and in 1992 he joined the reunited Brecker Brothers, playing on seven of the eleven tracks of Return of the Brecker Brothers.

Standards (And Other Songs) (1992) put him in front of an acoustic rhythm section with Jay Anderson and Al Foster and won him Guitar Player's readers' and critics' poll as jazz guitarist of the year for 1993. It began a long Atlantic run: Is What It Is (1994), Between the Lines (1996), Give and Take (1997) with John Patitucci, Jack DeJohnette, Michael Brecker and David Sanborn, Play (1999), which set him against Bill Frisell and John Scofield on separate tracks, and Voices (2001), his first record built around wordless singing. He moved to the German label ESC for These Times (2003), recorded at Avatar Studios that January with Richard Bona, Kenny Garrett and Vinnie Colaiuta, then to Heads Up for Who Let the Cats Out? (2006), which brought in Roy Hargrove and Meshell Ndegeocello, and Big Neighborhood (2009), a record assembled session by session with a different band on almost every track: Steve Vai on two, Eric Johnson on two more, Esperanza Spalding and Terri Lyne Carrington on three, John Medeski, Chris Wood and Billy Martin on two, and Chris Minh Doky, Cindy Blackman and Randy Brecker on the last. He was co-billed with the Yellowjackets on Lifecycle (2008), for which he also wrote "Double Nickel" and "Dreams Go," and toured with them into 2009.

On July 3, 2016, hailing a cab in New York on his way to a European tour, Stern tripped over construction debris and fell, fracturing both humerus bones and doing nerve damage to his right hand that left him unable to grip a plectrum. He had surgery, eleven screws going into one arm, and was back on a bandstand by late October, playing seated during Chick Corea's two-month residency at the Blue Note and wearing a glove fitted with Velcro to hold a Velcro-backed pick. After a second operation he settled on a blunter solution, gluing and taping the pick directly to his fingers, and recovered enough control to keep his speed and articulation. Trip, recorded at Spin Studio in Long Island City in January and March 2017 and named with characteristic bluntness, was made that way, with Randy Brecker, Wallace Roney, Bob Franceschini, Bill Evans, Victor Wooten, Tom Kennedy, Dave Weckl, Dennis Chambers and Lenny White. He has kept working since: Eleven (Concord Jazz, 2019), a co-billed record with the Jeff Lorber Fusion on which he plays nine of the ten tracks, and Echoes and Other Songs (Artistry Music and Mack Avenue, September 13, 2024), with Christian McBride, Antonio Sanchez, Dennis Chambers, Richard Bona, Arto Tuncboyaciyan and Leni Stern on ngoni, and with Jim Beard, his producer and keyboard player since the 1980s, in the piano chair on what became one of Beard's last sessions.

Stern's albums have drawn six Grammy nominations for Best Contemporary Jazz Album, for Is What It Is, Between the Lines, Voices, Who Let the Cats Out?, Lifecycle and Big Neighborhood. He was named jazz guitarist of the year by Guitar Player in 1993, took the Orville H. Gibson award for best jazz guitarist in 1997, received the Miles Davis Award at the Festival International de Jazz de Montreal in June 2007, was placed on DownBeat's list of the 75 great guitarists in 2009, and was given Guitar Player's Certified Legend award on January 21, 2012.

Stern's sound is the point of recognition before any phrase is: a Telecaster-shaped solidbody through a heavily chorused, slightly overdriven signal, wide stereo delay, and an attack that stays legato even at high speed. What he plays over it is a genuine hybrid. The long, saxophone-like eighth-note lines and the chromatic approach notes come from bebop and from his admiration for Jim Hall's chord voicings; the bends, the repeated figures and the willingness to sit on one note come from B.B. King and the rock players he learned from first, and he has never treated the two vocabularies as separate rooms. His writing is equally consistent, built on blues forms stretched into odd lengths, minor vamps and singable heads that his bands have kept in rotation for decades: "Chromazone," from Time in Place, became the title track of a Danish Radio Big Band album recorded in Copenhagen in January 2007 with Stern as guest soloist, and "Chief" is his elegy for Miles Davis. He has been credited on records by musicians as far apart as George Coleman, Ron Carter and Jimmy Cobb on one side and Steve Vai on the other, which is less a matter of range than of one style being genuinely legible in both places. The 2016 fall and its aftermath changed the mechanics without changing the music: playing with the pick glued to his fingers, he made Trip and Echoes and Other Songs, and the phrasing on both is recognisably what it was on Atlantic in 1988.