Holmes began DJ-ing in Belfast from the age of 15. His first hit was the 1992 track "De Niro" as the Disco Evangelists with Ashley Beedle and Lindsay Edwards (who later joined Tin Tin Out). In the early to mid-1990s he ran two club nights in the Belfast Art College known as Sugar Sweet and Shake Yer Brain. Orbital wrote the track "Belfast", released on their debut album Orbital, after playing at Sugar Sweet.
Holmes released This Film's Crap Let's Slash the Seats, in July 1995. At the time he described the album as being inspired by movies and movie soundtracks, a recurring theme throughout Holmes' work (see Discography). The opening track, "No Man's Land", featured on the soundtrack to the film, Pi. In the same year, he also provided the ambient links between the songs on the album Infernal Love by Therapy?. In 1997, Holmes released Let's Get Killed. Many of the tracks featured Brazilians dancing in the streets of New York, recorded by Holmes using a minidisc recorder. The album's first single, "My Mate Paul," was Holmes' first commercial success.
His 1997 Essential Mix, a mixture of northern soul, psychedelic funk and hip hop was voted mix of the year by Muzik magazine
In 1998, Danny DeVito commissioned him to do the score for Steven Soderbergh's film Out of Sight. He scored a second film for Soderbergh in 2001, including some songs from Let's Get Killed and Bow Down to the Exit Sign on the Ocean's Eleven remake.
After releasing a remix album, Come Get It I Got It, in 2002, Holmes released David Holmes Presents The Free Association. This was a departure for the artist as all his previous work had been solo. The Free Association featured four other bandmates who toured with Holmes after the album was launched.
Before beginning his musical career, Holmes worked as a hairdresser and chef. He also briefly owned and ran a café called Mogwai near the Queen's University of Belfast and, since 2009, has run an intimate club in South Belfast called The Menagerie.
In 2008, he composed the music for the "New iPhone" ad campaign. An album, The Holy Pictures, was released on 8 September 2008, from which the track "Holy Pictures" was selected for the soundtrack of Pro Evolution Soccer 2010. The first track from this album, "I Heard Wonders", also featured in the movie Cherrybomb and the Opening Ceremony of the 2012 Olympics to accompany the footage of David Beckham and Jade Bailey bringing the olympic flame up the River Thames by speedboat.
In April 2009, he topped the Irish Times' "50 Best Irish Acts Right Now".