Byrne was born into a family of Irish origin in Dumbarton, Scotland, to Tom and Emma Byrne. He was the elder of two children. Two years later, his parents moved to Hamilton, Ontario, Canada, and then to Arbutus, Maryland, when he was 8 or 9 years old. His father worked as an electronics engineer. Before high school, David Byrne already knew how to play the guitar, accordion, and violin. He was rejected from his middle school’s choir because they claimed he was "off-key and too withdrawn". From a young age, Byrne had a strong interest in music. His parents say that he would constantly play his phonograph from age three and he learned how to play the harmonica at age five. In his journals he says, "I was a peculiar young man ... borderline Asperger's, I would guess."

He graduated from Lansdowne High School in southwest Baltimore County. Byrne started his musical career in a high school duo named Bizadi with Mark Kehoe. Their repertoire consisted mostly of songs such as "April Showers", "96 Tears", "Dancing On The Ceiling", and Frank Sinatra songs. Byrne then attended the Rhode Island School of Design for one year before dropping out and forming a band called "The Artistics" with fellow RISD student Chris Frantz. The band dissolved within a year, and the two moved to New York together with Frantz's girlfriend Tina Weymouth. Unable to find a bass player in New York, Frantz and Byrne persuaded Weymouth to learn to play the bass guitar. She admits that the encouragement she received from Byrne, Frantz, and famed trumpet player Don Cherry (who lived in their building), was critical as to her grasp of the instrument.

After some practice and playing and together they founded the group Talking Heads which had its first gig in 1975. Multi-instrumentalist Jerry Harrison joined the group in 1977. During his time in the band, Byrne took on outside projects, collaborating with Brian Eno in 1981 on the album My Life in the Bush of Ghosts, which attracted considerable critical acclaim and featured a groundbreaking use of sampling.

While working on the film True Stories, Byrne met costume designer Adelle Lutz whom he married in 1987. They have a daughter, Malu Abeni Valentine Byrne, born in 1989. Byrne and Lutz divorced in 2004.

Byrne currently lives in New York City.

In 1981, Byrne partnered with choreographer Twyla Tharp, scoring music he wrote that appeared on his album, The Catherine Wheel for a ballet with the same name, prominently featuring unusual rhythms and lyrics. Productions of The Catherine Wheel appeared on Broadway that same year. In Spite of Wishing and Wanting is a soundscape David Byrne produced for the Belgian dance company Ultima Vez.

His work has been extensively used in movie soundtracks, most notably in collaboration with Ryuichi Sakamoto and Cong Su on Bernardo Bertolucci's The Last Emperor, which won an Academy Award for Best Original Score. In 2004, Lead Us Not Into Temptation included tracks and musical experiments from his score to Young Adam. Byrne also wrote, directed, and starred in True Stories, a musical collage of discordant Americana released in 1986, as well as producing most of the film's music. Byrne also directed the documentary Île Aiye and the concert film of his 1992 Latin-tinged tour titled Between the Teeth. He was chiefly responsible for the stage design and choreography of Stop Making Sense in 1984. Byrne added "Loco de Amor" (Crazy for Love) with Celia Cruz to Jonathan Demme's 1986 film Something Wild.

Byrne wrote the Dirty Dozen Brass Band-inspired score for Robert Wilson's Opera The Knee Plays from A Tree Is Best Measured When It Is Down. Some of the music from Byrne's orchestral album The Forest was originally used in a Wilson-directed theatre piece with the same name. The Forest premiered at the Theater der Freien Volksbühne, Berlin in 1988. It received its New York premiere in December 1988 at BAM, the Brooklyn Academy of Music. The Forestry Maxi-single contained dance and industrial remixes of pieces from The Forest by Jack Dangers, Rudy Tambala, and Anthony Capel.

In 1990, Byrne contributed a version of "Don't Fence Me In" to the AIDS benefit compilation album Red Hot + Blue: A Tribute to Cole Porter produced by the Red Hot Organization. Byrne appeared as a guest vocalist/guitarist for 10,000 Maniacs during their MTV Unplugged concert, though the songs in which he is featured were cut from their following album. One of them, "Let the Mystery Be", appeared as the fourth track on 10,000 Maniacs' CD single "Few and Far Between". Byrne worked with the "Queen of Tex-Mex", Tejano superstar Selena, writing, producing and singing a song ("God's Child (Baila Conmigo)"), included on Selena's last album, "Dreaming of You", before her death. Byrne was the host of Sessions at West 54th during its second of three seasons and collaborated with members of Devo and Morcheeba to record the album Feelings in 1997.

Byrne founded the world music record label Luaka Bop in 1990. It was originally created to release Latin American compilations, but it has grown to include music from Cuba, Africa, the Far East and beyond, releasing the work of artists such as Cornershop, Os Mutantes, Los De Abajo, Jim White, Zap Mama, Tom Zé, Los Amigos Invisibles and King Chango.

Byrne is also a visual artist whose work has been shown in contemporary art galleries and museums around the world since the 1990s. Represented by the Pace/MacGill Gallery in New York, he has also created public art installations, many of them anonymously. In 2010 his original art work is due to be featured in the exhibition The Record: Contemporary Art and Vinyl at the Nasher Museum of Art at Duke University.

Byrne is known for his activism in support of increased cycling, and for having used a bike as his main means of transport for most of his life, especially cycling around New York. In 2008, Byrne designed a series of innovative bicycle parking racks in the form of image outlines corresponding to the areas in which they were located, such as a dollar sign for Wall Street and an electric guitar in Williamsburg, Brooklyn. Byrne worked with a manufacturer that would construct the racks in exchange for the chance to sell them later as artworks, and the racks remained on the streets for about a year. He says that he cycled when he was in high school and was able to get back into the sport in the late 1970s. He likes the freedom and exhilarating feeling cycling gives him. He has written widely on cycling, including a 2009 book, Bicycle Diaries. In August 2009, he auctioned his Montague folding bike in order to raise money for the London Cycling Campaign.

In 2001 a censored version of Byrne's single “Like Humans Do” was selected by Microsoft as the sample music for Windows XP to demonstrate Windows Media Player (not included in SP2 installs). The next year, he provided vocals for a track, "Lazy" by X-Press 2, which reached number 2 in the United Kingdom and number 1 on the U.S. Dance Charts. Byrne said in an interview in BBC Four Sessions's coverage of his Union Chapel performance that “Lazy” was number 1 in Syria.

In April 2003, Byrne appeared as himself in an episode of The Simpsons, "Dude, Where's My Ranch?". Later in the year, Byrne released the book Envisioning Emotional Epistemological Information (ISBN 3-88243-907-6). together with a companion DVD. The work included artwork composed entirely in Microsoft PowerPoint. It includes one image that depicts, according to Byrne, "Dan Rather's profile. Expanded to the nth degree. Taken to infinity. Overlaid on the back of Patrick Stewart's head."

Byrne's solo album, Grown Backwards, was released on March 16, 2004 by Nonesuch Records. This album used orchestral string arrangements, and includes two operatic arias. He also launched a North American and Australian tour with the Tosca Strings. This tour ended with Los Angeles, San Diego and New York shows in August 2005. The following year, his singing was featured on "The Heart's a Lonely Hunter" on The Cosmic Game by Thievery Corporation.

In 2005, Byrne initiated his own internet radio station, Radio David Byrne. Each month, Byrne posts a playlist of music he likes, linked by themes or genres. Byrne's playlists have included African popular music; Country music classics; Vox Humana; Classical opera, and film scores from Italian movies. Byrne also posts personal comments on the music and, occasionally, on the state of the recorded music industry. In July 2007, Byrne posted the following comment:

Returning to this work in the theatre, in late 2005 Byrne and Fatboy Slim began work on Here Lies Love, a disco opera or song cycle about the life of Imelda Marcos, the controversial former First Lady of the Philippines. Some music from this piece was debuted at Adelaide Festival of Arts in Australia in February 2006 and the following year at Carnegie Hall on February 3, 2007.

Byrne and Eno's influential 1981 album My Life in the Bush of Ghosts was re-released for its 25th anniversary in early 2006, with new bonus tracks. In keeping with the spirit of the original album, two of the songs' component tracks were released under Creative Commons licenses and a remix contest site was launched. Later that same year, Byrne released Arboretum, a sketchbook facsimile of his Tree Drawings, published by McSweeney's. He also had an exhibition of his chairs ... drawings, photographs, sculptures, and embroideries ... at Pace/MacGill Gallery, NYC. In 2007, David Byrne provided a cover of The Fiery Furnaces' song "Ex-Guru" for a compilation to celebrate the 15th birthday of Thrill Jockey, a Chicago-based label.

In April 2008 Byrne took part in the Paul Simon retrospective concert series at BAM performing "You Can Call Me Al" and "I Know What I Know" from Simon's Graceland album.In 2008, Byrne and his production team programmed the Battery Maritime Building, a 99-year-old ferry terminal in Manhattan, to play music. Essentially Byrne took the old New York City building, hooked the entire structure - pipes, heaters, pillars and all, electronically to an old pipe organ, and made a playable musical instrument of it, for a piece called "Playing the Building". This project was also installed in 2005 in Stockholm, Sweden, and at the London Roundhouse in 2009. It bears similarities to a series of installations performed by New Zealand and Detroit based artists Alastair Galbraith and Matt De Genaro, recorded on their 1998 record Wire Music and 2006 follow-up Long Wires in Dark Museums, Vol. 2. Byrne says that the point in this project was to allow people to experience art first hand, by creating the music with the organ, rather than simply looking at it.Byrne and Eno reunited for 2008's Everything That Happens Will Happen Today and Byrne assembled a band to tour the album and other collaborations between the two through late 2008. He assembled a band to tour worldwide for the album for a six-month period from late 2008 through early 2009 on the Songs of David Byrne and Brian Eno Tour. The day after that album was released, Hymnal - his soundtrack to season two of Big Love was made available. These two albums constituted the first releases on his personal independent record label Todo Mundo. In the same year, Byrne performed at the Austin City Limits festival.

He is featured on the tracks "Money" and "The People Tree", on N.A.S.A.'s 2009 album The Spirit of Apollo. Also in 2009, David Byrne appeared on HIV/AIDS charity album Dark Was the Night for Red Hot Organization. He collaborated with Dirty Projectors on the song "Knotty Pine". In the same year, Byrne performed at the Bonnaroo Music Festival in Manchester, Tennessee. He also was a signator of a letter protesting the decision of the Toronto International Film Festival to choose Tel Aviv as the subject of its inaugural City-to-City Spotlight strand.

In 2010 David Byrne songs were featured on the soundtrack of Oliver Stone's Wall Street Money Never Sleeps.

Selected discography

• My Life in the Bush of Ghosts (with Brian Eno) (1981)
• Rei Momo (1989)
• The Forest (1991)
• Uh-Oh (1992)
• David Byrne (1994)
• Feelings (1997)
• Look into the Eyeball (2001)
• Grown Backwards (2004)
• Everything That Happens Will Happen Today (with Brian Eno) (2008)

Books

• True Stories (1986)
• Strange Ritual, Chronicle Books (1995)
• Your Action World (1999)
• The New Sins (Los Nuevos Pecados) (2001)
• David Byrne Asks You: What Is It? Smart Art Press (2002)
• Envisioning Emotional Epistemological Information with DVD (2003)
• Arboretum, (2006)
• Bicycle Diaries (2009)

Film

• Stop Making Sense - concert movie from Talking Heads tour (1984)
• True Stories (1986)
• Ile Aiye (The house of life) - Documentary (1989)
• Here Lies Love - with concept album in collaboration with Norman Cook (released 2010)
• Ride, Rise, Roar - music documentary of his concert tour with Brian Eno (released 2010)