Des Barres has appeared in over 100 different TV shows and almost 30 movies in his career. He first started acting at 8 years old as 'The Nux Bar Kid' on posters all over England. He appeared (uncredited) in the 1966 film starring Tony Curtis, Drop Dead Darling. His first credited film role was as a supporting cast member in the classic 1967 film To Sir, with Love, playing an East End pupil who always wears dark sunglasses indoors and out, followed by a few other minor roles before he decided to pursue a career in music instead. He later concentrated his energies on acting again and was quickly cast in Ghoulies (1984) as cult leader Malcolm Graves, and Nightflyers (1987) as a charismatic empath. He worked opposite Clint Eastwood in 1989's Pink Cadillac. His other film roles have included Midnight Cabaret (1990), Under Siege (1992), Waxwork II: Lost in Time (1992), A Simple Twist of Fate (1994), and Sugar Town (1999). He also appeared in the 2004 film Catch That Kid and had a brief part in David Lynch's classic 2001 film Mulholland Drive.

A heavy alcohol and drug abuser during the 1970s, Des Barres has been sober since June 1981. In the mid-80s he was one of the founding members of Rock Against Drugs. He later did volunteer addiction counseling and worked with homeless teens. Des Barres has also organised and hosted the annual Don't Knock the Rock Film Festival, which first took place in 2003.

Des Barres formed his first teenage band, the Orange Illusion, with Nicholas Young, Darryl Read, and Kit Williams, whilst they were all attending Corona Academy Stage School studying to be actors. The lineup, despite being broken up by the school's agent Hazel Malone, all went on to do greater things individually. Des Barres then formed Silverhead in England in 1972. They recorded two albums, and toured the US, Europe, and Japan before disbanding in 1974.

After moving to Los Angeles, he formed the band Detective in 1975. They recorded two albums that were released on Led Zeppelin's Swan Song Records label, before breaking up in 1978.

Married in England, he divorced his first wife - Wendy - after meeting Pamela in 1974. He married Pamela on 29 October 1977; the couple were divorced in 1991, remaining friends. Their son, Nicholas Dean Des Barres, was a contributor to the video game magazine GameFan, writing many of his articles under the pseudonym "Nick Rox"; Nick also designed the Resident Evil film poster, and is currently a game Writer at video game developer PlatinumGames.

A solo album, I'm Only Human, followed in 1980, with a solo tour of the US and UK. The album was recorded on Dreamland Records and produced by Mike Chapman (known for producing records by The Sweet, Blondie, Suzi Quatro, and The Knack). His Musicians at this time were the session band Zoo Drive featuring John Goodsall (guitars), Paul Delph (keyboards), Doug Lunn (bass), and Ric Parnell (drums). On the recording and in significant gigs Nigel Harrison (of Blondie) replaced Doug Lunn on bass.

He was part of the band Chequered Past from 1982 to 1985, which included Steve Jones from [The] Sex Pistols, Clem Burke and Nigel Harrison from Blondie, and Tony Sales of Todd Rundgren (Runt) and Tin Machine fame.

In 1983, he wrote and recorded the song "Obsession" together with Holly Knight, which later became a No.6 Billboard Top 40 hit when covered by Animotion in 1985.

Des Barres met the members of Duran Duran when Chequered Past opened for a few shows during their 1984 tour. In 1985, when Robert Palmer withdrew from the Duran Duran side project Power Station just before their American summer tour, Des Barres was chosen to take his place as lead vocalist. He performed live with them for several months before they disbanded, including a set broadcast to millions at the 1985 Live Aid charity concert in Philadelphia. Des Barres' friendship with actor Don Johnson got Power Station a guest appearance on Johnson's TV show Miami Vice. He wrote one song with the band, "We Fight For Love" which appears on the Soundtrack to the film Commando.

He released a second solo album called Somebody Up There Likes Me in 1986, which featured contributions by former bandmates Steve Jones (Sex Pistols) and Andy Taylor (Duran Duran).

On television, besides the role of Murdoc in MacGyver, Des Barres was also a lead cast member of The New WKRP in Cincinnati during the 1991-92 season, as part of a husband-and-wife morning team. He had previously appeared on the original WKRP in Cincinnati as the lead singer of a punk band, Scum of the Earth. During this same time, he played a gay man (Leon's boyfriend) in two episodes of Roseanne. He also played one of Darlene's baby's doctors on one of the final episodes of the series. Some of his dozens of television appearances include Seinfeld, Renegade, ALF, Ellen, Nip/Tuck, Just Shoot Me!, Hart To Hart, My Sister Sam, Lois & Clark (which reunited him with another MacGyver recurring-character alumna, Teri Hatcher - the two had even appeared together in two MacGyver episodes), JAG, Melrose Place, Nash Bridges, Northern Exposure, Rockford Files, Sledge Hammer!, Sliders, St. Elsewhere, 21 Jump Street, The Pretender, Dead Like Me, Frasier, Hawaii, Bones, and NCIS (in the Season 10 episode "Phoenix").

Although focusing more on his acting career in the following years, Des Barres continued to write music and perform live with various bands in the Los Angeles area. In 1996 - 1997, he played in Vince Lightning and the Spectaculars, which included Stray Cats Drummer Slim Jim Phantom. From 1998 - 2000, he had a band called The Usual Susspects with Steve Jones and Mick Rossi.

In 2001, Des Barres formed Down Boy together with Paul McCartney's Guitarist Brian Ray. In 2006 - 2007, he fronted a 10-piece soul band called Michael Des Barres and Free Love Foundation.

In 2011, he formed The Michael Des Barres Band, which included Jebin Bruni, David Goodstein, Paul Ill, and Eric Schermerhorn; the band released an album entitled Carnaby Street in June 2012.

On 23 October 2013 Michael joined the Los Angeles Philharmonic for the world premiere of 200 Motels: The Suites, by Frank Zappa, in which he appeared as Rance, the narrator.

On 7 April 2015 Des Barres released a solo album, The Key to the Universe. Produced by Bob Rose at The Forum Music Village in Rome, the album reunites Des Barres with Nigel Harrison (former Bassist of Blondie and Silverhead) on bass and guitar, in addition to Clive Deamer (Portishead, Robert Plant) on drums, and Dani Robinson on guitar.

On the episode "Murdoc + Handcuffs" of MacGyver (2016), airing February 2, 2018, he plays Nicholas Helman, who mentored Murdoc and wants him dead.

Currently, Des Barres hosts "The Michael Des Barres Program" every weekday morning on Little Steven’s Underground Garage (SiriusXM Channel 21).