Nick Lowe began his recording career in 1966 as a member of Kippington Lodge, founded with his friend Brinsley Schwarz, which released a few singles on Parlophone. Three years later Kippington Lodge had changed its name to Brinsley Schwarz and its musical focus to country- and blues-rock. Lowe's best-known song from the Brinsley Schwarz era is probably either "(What's So Funny 'Bout) Peace, Love, and Understanding," which was a major hit for Elvis Costello in 1979, or "Cruel to Be Kind," a song the other band members rejected but was later a solo hit for Lowe.

After leaving Brinsley Schwarz in the mid-1970s, Lowe began playing in Rockpile with Dave Edmunds. In August 1976, Lowe released "So It Goes" b/w "Heart of the City", the first single on the Stiff Records label where he was in-house producer (the label's first EP was Lowe's 1977 four-track release Bowi, apparently named in response to David Bowie's contemporary LP Low) . On this and other labels, Lowe would go on to produce The Damned's Damned, Damned, Damned and many albums by Elvis Costello, including My Aim Is True, This Year's Model, and Armed Forces. Upon moving from Stiff to Jake Riviera's Radar and F-Beat labels, Lowe became extremely selective in his choice of production tasks.

Because the two main writers in Rockpile had contracts with different record labels and managers, albums were always credited to either Lowe or Edmunds, so there is only one official Rockpile album, from the very end of the collaboration—1980's Seconds of Pleasure, featuring the Lowe songs "When I Write The Book" and "Heart"—but all of Lowe's and Edmunds' solo albums from the period were effectively Rockpile albums. Rockpile's demise was hastened by a number of conflicts between Lowe's and Edmunds' respective managers, not Lowe and Edmunds themselves.

Lowe's best-known song from this era is probably "I Knew the Bride When She Used to Rock 'n' Roll" (the verse structure and topic adapted from Chuck Berry's "You Never Can Tell" (a.k.a. "Teenage Wedding"), but adding a chorus section to Berry's verse-after-verse format). On the 1977 Live Stiffs compilation with a pickup band called Last Chicken in the Shop, he virtually sneers out his contempt for all concerned; in 1985, fronting Nick Lowe and His Cowboy Outfit on the album The Rose of England, he hasn't changed the words, but the tone is entirely different, even affectionate (the song was produced by Huey Lewis, while his band The News played on the track).

Lowe was quoted as saying that he had "escaped from the tyranny of the snare drum", when explaining his move away from regular pop music that would get played on mainstream radio.

Other well-known Lowe songs from this time include "I Love The Sound of Breaking Glass," "All Men Are Liars," and "Cruel to Be Kind,", co-written with Ian Gomm and originally recorded with Brinsley Schwarz, a re-recording of which was his only US Top 40 hit, reaching #12 on the Billboard charts in 1979.

In 1979, Lowe married country singer Carlene Carter, daughter of country singers Carl Smith and June Carter Cash and step-daughter of Johnny Cash. He adopted her daughter, Tiffany Anastasia Lowe. The marriage with Lowe lasted until the mid '80s, but they remained friends, and Lowe remained close to the Carter/Cash family; he and Johnny Cash played and recorded together, and Cash recorded several of his songs. In 2005 Nick Lowe welcomed his first son, Roy Lowe.

After the demise of Rockpile, Lowe toured for a period with his band Noise To Go and later with The Cowboy Outfit, which also included the noted keyboard player Paul Carrack. Lowe was also a member of the short-lived mainly studio project Little Village with John Hiatt, Ry Cooder, Trevor Whittaker, and Jim Keltner.

In 1992, "(What's So Funny 'Bout) Peace, Love, and Understanding" was covered by Curtis Stigers on the soundtrack album to The Bodyguard, an album that sold over 15 million copies.

1994 saw the release of the album The Impossible Bird the first instalment of what has become known as ‘The Brentford Trilogy’. The second part is 1998s Dig My Mood and the third is 2001s The Convincer, on all of these albums the core musicians aiding and abetting Nick are Bobby Irwin and Geraint Watkins. Guitar duties on The Impossible Bird are taken up by Bill Kirchen and for the other two releases Steve Donnelly steps in.

June 2007 sees the release of At My Age a beautifully laid-back and soul-stirring listening experience, it is coloured with horns, strings, and country flourishes. This senior service for the ancient and modern is served up largely by Nick, Bobby, Geraint and Steve Donnelly along with Matt Radford on double bass, Matt Holland on Trumpet and Flugelhorn and Martin Winning on tenor sax and clarinet. Guest appearances are made by Chrissie Hynde, Chris Barber and Bill Kirchen, amongst others.