Matteo Mancuso was born in Palermo on November 22, 1996. His father, Vincenzo Mancuso, is a professional guitarist and producer who has worked with well-known Italian artists, and he began teaching the boy guitar at the age of ten. Matteo was on a stage at eleven and played the Castelbuono Jazz Festival in Sicily at twelve, in 2009. At music high school he studied classical guitar and transverse flute, and in his teens he and his father worked up a duo programme of Django Reinhardt's repertoire and contemporary jazz standards, while his own listening ran to Led Zeppelin, Deep Purple, Rush, Yes and Dream Theater.

His first real notice came in 2017. After a performance at the Umbria Jazz Festival in Perugia he was awarded a scholarship to the Berklee College of Music in Boston, and that year he formed the trio SNIPS with bassist Riccardo Oliva and drummer Salvatore Lima, a fusion group built on rearrangements of fusion standards and originals. Its YouTube version of "The Chicken" passed two million views. SNIPS played Musikmesse in Frankfurt in 2018 and Umbria Jazz again that year, and in 2019 Mancuso appeared at the NAMM Show in Anaheim as a Yamaha artist, took part in the Asia International Guitar Festival in Bangkok and gave clinics in Moscow, St. Petersburg and Perm. The same year he is credited on guitar on drummer Virgil Donati's album Ruination. In June 2022 he graduated with honours in jazz guitar from the Palermo Conservatory of Music.

In 2020 he put together a new trio with bassist Stefano India and drummer Giuseppe Bruno, and introduced it online with a video of Jaco Pastorius's "Havona." When live work resumed in 2021 the group played two sold-out nights at the Blue Note in Milan. In 2022 the trio appeared at the Bremen International Festival, Rome's Auditorium Parco della Musica, the Uppsala Jazz Festival and the Spoleto Jazz Festival. That summer Al Di Meola invited him onstage at the Eddie Lang Jazz Festival in Monteroduni for acoustic readings of Chick Corea's "Spain" and Di Meola's "Elegant Gypsy," and Mancuso and keyboardist Luca Zabbini sat in with the Italian progressive band PFM at Lugano Estival Jazz. The live album of that concert, The Event (Live in Lugano Estival Jazz), was released on Aerostella in May 2023.

The Journey, his debut as a leader, was released on July 21, 2023 by The Players Club, a division of Mascot Label Group. It collects nine original instrumentals that range from modern jazz ("Polifemo") to hard rock and prog ("Drop D"). It was recorded in Sicily at Fico d'India Studios in Casteldaccia by his father, who also co-wrote "Polifemo" and "Blues for John," with the trio of Stefano India and Giuseppe Bruno and, on two tracks, Riccardo Oliva and drummer Gianluca Pellerito. Guitar World placed it fourth on its list of the best guitar albums of 2023 and ranked "Silkroad" seventh among the year's best guitar solos. He toured the United States from January 25 to February 4, 2024, played the NAMM Show again that year, and was a featured guest at Steve Vai's Vai Academy 7.0 guitar camp in Orlando, where he played with Vai's band and keyboardist Jordan Rudess. A baritone-guitar single, "Paul Position," followed in July 2024.

In 2026 he appeared on Tutta Vita Live with the Stefano Bollani All Stars, the live version of Stefano Bollani's project with Enrico Rava and Paolo Fresu among its players, and was featured on one track of Jack Gardiner's Kintsugi. His second album, Route 96, was released on April 24, 2026 by Music Theories Recordings, part of Mascot Label Group. Its title nods to his birth year and to the 96 kHz sample rate Vai urged him to record at. Oliva plays bass and Pellerito drums on eight of its nine tracks, with Vai guesting on "Solar Wind," the gypsy-jazz guitarist Antoine Boyer on "Isla Feliz," and keyboardist Valeriy Stepanov on the bonus track, a new version of "The Chicken." A European tour followed the release. Mancuso is 29.

Mancuso plays electric guitar without a pick. His right hand works like a classical or flamenco guitarist's, using a free stroke with the index and middle fingers, and he alternates between supported and unsupported strokes. He plays a Yamaha Revstar, and Yamaha has built a signature model around him. His material crosses lines: The Journey holds modern jazz, fusion, hard rock, prog and acoustic pieces, and AllMusic's biography reports that he describes himself as neither a shredder nor a jazz player in the strict sense. That puts him in the crossover territory between instrumental rock guitar and jazz-fusion, which is also where much of his audience comes from, since his reputation began on YouTube. The jazz credentials are real, though: a conservatory degree in jazz guitar, Umbria Jazz and Blue Note engagements, and work with Al Di Meola and Stefano Bollani. Steve Vai, Di Meola, Joe Bonamassa and Tosin Abasi have all praised him in public, and Bonamassa said he had not seen the instrument reinvented like this since Stanley Jordan. Mascot's biography names his father, Django Reinhardt's repertoire and the 1970s hard rock and prog bands as the lines running into his playing, and his 2020 trio video of Jaco Pastorius's "Havona" points to the fusion tradition behind it.