James MacMillan read music at Edinburgh University and took Doctoral studies in composition at Durham University with John Casken. After working as a lecturer at Manchester University, he returned to Scotland and settled in Glasgow. The successful premiere of Tryst at the 1990 St Magnus Festival led to his appointment as Affiliate Composer of the Scottish Chamber Orchestra. Between 1992 and 2002 he was Artistic Director of the Philharmonia Orchestra's Music of Today series of contemporary music concerts. MacMillan is internationally active as a conductor, working as Composer/Conductor with the BBC Philharmonic between 2000 and 2009, and appointed Principal Guest Conductor of the Netherlands Radio Chamber Philharmonic from 2010. He was awarded a CBE in January 2004.

In addition to The Confession of Isobel Gowdie, which launched MacMillan's international career at the BBC Proms in 1990, his orchestral output includes his first percussion concerto Veni, Veni, Emmanuel, premiered by Evelyn Glennie in 1992 and which has since received over 500 performances worldwide. MacMillan's music has been programmed extensively at international music festivals, including the Edinburgh Festival in 1993 and 2019, the Bergen Festival in 1997, the South Bank Centre's 1997 Raising Sparks festival in London, the Queensland Biennial in 1999, the BBC Barbican Composer Weekend in 2005 and the Grafenegg Festival in 2012. A documentary film portrait of MacMillan by Robert Bee was screened on ITV's South Bank Show in 2003.

Works by MacMillan from the 1990s also include Seven Last Words from the Cross for chorus and string orchestra, screened on BBC TV during Holy Week 1994, Inés de Castro, premiered by Scottish Opera in 1996 and given a second production in 2015, a triptych of orchestral works commissioned by the London Symphony Orchestra: The World's Ransoming, a Cello Concerto for Mstislav Rostropovich, and Symphony: 'Vigil' premiered under the baton of Rostropovich in 1997, and Quickening for vocal ensemble, chorus and orchestra, co-commissioned by the BBC Proms and the Philadelphia Orchestra.

MacMillan works composed in the 2000s include Piano Concerto No.2 first performed with choreography by Christopher Wheeldon at New York City Ballet, A Scotch Bestiary commissioned to inaugurate the new organ at Disney Hall with soloist Wayne Marshall and the Los Angeles Philharmonic conducted by Esa-Pekka Salonen, and The Sacrifice premiered and toured by Welsh National Opera in 2007. His St John Passion, co-commissioned by the LSO, Royal Concertgebouw Orchestra, Boston Symphony Orchestra and Berlin Radio Choir, was premiered under the baton of Sir Colin Davis in 2008.

The past decade has brought a successful sequence of concertos: for violinist Vadim Repin, pianist Jean-Yves Thibaudet (his third piano concerto), oboist Nicholas Daniel, violist Lawrence Power, percussionist Colin Currie (his second percussion concerto) and trombonist Jörgen van Rijen. Orchestral scores have included Woman of the Apocalypse premiered by Marin Alsop at the Cabrillo Festival and Symphony No.4 premiered at the 2015 BBC Proms. Works with choir include a festive setting of the Gloria (to mark the 50th anniversary of the consecration of Coventry Cathedral), St Luke Passion for chorus and chamber orchestra, A European Requiem for soloists, chorus and orchestra, Stabat Mater for choir and string orchestra, The Sun Danced for soprano, choir and orchestra, his setting of wartime poetry All the Hills and Vales Along for tenor, choir, brass band and strings, the 40-voice motet Vidi aquam and Christmas Oratorio for soloists, chorus and orchestra. His one-act chamber opera Clemency has been performed in London, Edinburgh, Boston and Amsterdam. 2014 saw MacMillan launching a new annual music festival in his home town of Cumnock and in 2017 a city-wide celebration of his music took place in Glasgow.

In terms of recordings, the Koch Schwann disc of The Confession of Isobel Gowdie and Tryst won the 1993 Gramophone Contemporary Music Record of the Year Award, and the BMG recording of Veni, Veni, Emmanuel won the 1993 Classic CD Award for Contemporary Music. MacMillan discs on the BIS label include the complete Triduum conducted by Osmo Vänskä, the clarinet concerto Ninian and the trumpet concerto Epiclesis. A MacMillan series on Chandos with the BBC Philharmonic includes The Berserking, Symphony No.3: 'Silence' which won a Classical Brit award in 2006, Quickening and The Sacrifice. Other acclaimed recordings include Mass and Seven Last Words from the Cross on Hyperion, Stabat Mater on Coro, and discs on the Naxos, Black Box, Linn, LSO Live and Challenge Classics labels.

James MacMillan was awarded a Knighthood in the 2015 Queen's Birthday honours and his anthem Who Shall Separate Us? was commissioned for the 2022 funeral of HM Queen Elizabeth II. He is published exclusively by Boosey & Hawkes.