Miguel Zenón was born December 30, 1976, in San Juan, Puerto Rico. He trained classically on alto saxophone for six years at the Escuela Libre de Música under Ángel Marrero before moving to Boston to attend Berklee College of Music, graduating in 1996, and later earning a master's degree in performance from the Manhattan School of Music in 2001.

In 1999, while still establishing himself in New York, Zenón co-founded a working quartet with drummer Antonio Sanchez, bassist Hans Glawischnig, and pianist Luis Perdomo (Henry Cole replaced Sanchez on drums in 2005, after Sanchez joined the Pat Metheny Group). The quartet documented its debut on Looking Forward (2001, Fresh Sound New Talent), which also featured guest spots from trumpeter Diego Urcola, tenor saxophonist David Sánchez, and guitarist Ben Monder. In 2004, at 27, Zenón became the youngest founding member of the SFJAZZ Collective, the rotating all-star repertory octet built each season around new arrangements of a single composer's book plus new group compositions; he held the group's alto saxophone chair for fourteen years, through 2018.

The same year he signed to saxophonist Branford Marsalis's label, Marsalis Music, releasing five albums between 2004 and 2011 (Ceremonial, Jíbaro, Awake, Esta Plena, and Alma Adentro) that established the core of his musical project: fusing the harmonic and rhythmic vocabulary of modern jazz with Puerto Rican folk forms, particularly jíbaro (mountain) music and plena. Esta Plena went furthest in that direction, built around plena's call-and-response vocal and percussion tradition with guest singer Héctor "Tito" Matos and percussionists Juan Gutiérrez and Obanilú Allende alongside his working quartet. In 2005 Zenón also joined bassist Charlie Haden's Liberation Music Orchestra for its Carla Bley-arranged album Not in Our Name (2005); Haden credited Zenón with suggesting the record's title. In 2008 he received both a MacArthur Fellowship and a Guggenheim Fellowship in the same year.

Starting in 2011, with the live album Oye!!! Live in Puerto Rico, Zenón began releasing music on his own label, Miel Music, and followed it with a run of more conceptually ambitious studio projects: Identities Are Changeable (2014), built around recorded interviews with Puerto Ricans living in New York about cultural identity, layered under the music itself; Típico (2016), a return to the standard quartet format with Perdomo, Glawischnig, and Cole after several records with expanded instrumentation; Yo Soy la Tradición (2018), scored for his quartet plus a string quartet; and Sonero: The Music of Ismael Rivera (2019), a tribute to the Puerto Rican salsa vocalist. Starting in 2021 he paired with longtime pianist Luis Perdomo for a duo project reinterpreting Latin American bolero standards, El Arte del Bolero, followed by El Arte del Bolero, Vol. 2 (2023), which won the Grammy Award for Best Latin Jazz Album in 2024. Golden City (2024) returned to a full band, featuring Diego Urcola on trumpet and valve trombone alongside guitarist Miles Okazaki, pianist Matt Mitchell, bassist Christopher Tordini, and drummer Dan Weiss. His most recent release, Vanguardia Subterránea: Live at the Village Vanguard (2025), is a live document that he also produced.

Alongside his own catalog, Zenón has recorded as a sideman on more than a hundred albums and has been a fixture as a jazz educator: he taught at Berklee, the Manhattan School of Music, and Princeton, served as Jazz Artist-in-Residence at Columbia University's Miller Theatre from 2020 to 2022, and is currently an Associate Professor in the Music Department at MIT. In 2011 he founded Caravana Cultural, a nonprofit that brings free jazz concerts and educational programming to towns across rural Puerto Rico that otherwise have little access to live jazz.

Zenón's playing and writing sit at the meeting point of two traditions he refuses to treat as separate: the harmonic complexity and improvisational freedom of modern jazz, and the rhythms and forms of Puerto Rican folk and popular music, from jíbaro and plena to bomba and the bolero. His alto sound is fast, angular, and rhythmically intricate, often built on long asymmetrical phrases played over shifting meters drawn from the folk material rather than jazz's usual 4/4 or swung triplet feel. He studied under pianist Danilo Pérez, a formative influence and mentor, and has cited alto saxophonists including Bunky Green and Steve Coleman as touchstones for his own harmonic language. Critics and peers have recognized this combination repeatedly: the Jazz Journalists Association has named him its Alto Saxophonist of the Year four times (2015, 2018, 2019, 2020) and its Arranger of the Year (2020) and Composer of the Year (2023), and JazzTimes named him Alto Saxophonist of the Year in its 2014 critics' poll.