Born in Natick, Massachusetts, into a Jewish family, Richman began playing music and writing his own songs in the mid-1960s. He became infatuated with the Velvet Underground, and in 1969 he moved to New York City, lived on the couch of their manager, Steve Sesnick, worked odd jobs and tried to break in as a professional musician. Failing at this, he returned to Boston.

(These last three live albums are from the same three 1971-3 performances, but add and subtract a few different songs. The last two, combined, contain all the songs.)

Later in 1972, the group also recorded with Producer Kim Fowley; these demos were eventually released in 1981 as The Original Modern Lovers. Despite playing live regularly, The Modern Lovers had a difficult time securing a recording contract. By late 1973, Richman wanted to scrap the recorded tracks and start again with a mellower, more lyrical sound, influenced by the laid-back local music he had heard when the band had a residency at the Inverurie Hotel in Bermuda earlier in the year. This stymied efforts to complete a debut album, and led to the breakup of the original Modern Lovers in February 1974.

In 1975, Richman moved to California to record as a solo singer/songwriter with Beserkley Records. His first released recordings appeared on 1975's Beserkley Chartbusters compilation, where he was backed by members of Earth Quake and The Rubinoos; these four songs also appeared on singles on the independent Beserkley label.

The album Jonathan Richman and The Modern Lovers was released in May 1976 (three months before the earlier The Modern Lovers sessions were finally released) but David Robinson left the group soon thereafter, due to frustration with Richman's quest for lower volume levels, and joined with Ric Ocasek in forming the band The Cars.

In the United Kingdom, Richman was recognised as a progenitor of the punk rock scene, and several of his singles became hits. "Roadrunner" reached Number 11 in the UK Singles Chart, and its follow-up, the instrumental "Egyptian Reggae", made Number 5 in late 1977. "Egyptian Reggae" was a version of Jamaican musician Earl Zero's reggae song "None Shall Escape the Judgment"; Zero was credited as co-writer on Richman's later versions of the track.

Back in Your Life was released in 1979 under the "Jonathan Richman and The Modern Lovers" moniker, but only about half the disc featured a backup band. The rest was solo work.

His first marriage was to Gail Clook of Vermont, in 1983, with whom he has a daughter, Jenny Rae. This marriage ended in divorce sometime shortly before the release of Surrender to Jonathan (1996).

Richman's work with the first incarnation of Modern Lovers is a major influence on punk rock. One critic called him the "Godfather of Punk". Artists as diverse as the Sex Pistols and Joan Jett have covered "Roadrunner". Boston ska-punk band Big D and the Kids Table have covered "New England" live and on their Gypsy Hill EP. A version of "Pablo Picasso" performed by Burning Sensations was included in the 1984 cult film, Repo Man. David Bowie covered "Pablo Picasso" on his album Reality. Velvet Underground founding member John Cale has a version of the song on his 1975 album, Helen of Troy, and continues to include the song in his live shows. Iggy Pop has performed "Pablo Picasso" live and wrote an extra verse for it. Echo and the Bunnymen covered "She Cracked" in concert in 1984 and 1985 and Siouxsie and the Banshees have a version of the song on Downside Up.

Richman's music has set the tone for many alternative rock bands, such as Violent Femmes, Galaxie 500, They Might Be Giants ("Roadrunner" reportedly inspired John Flansburgh to become a musician), Weezer, Tullycraft, Jens Lekman, singer Frank Black (who composed the tribute song "The Man Who Was Too Loud"), Brandon Flowers, Art Brut, Craig Finn of the Hold Steady & Lifter Puller, Mac Demarco and Nerf Herder who composed a song about him, titled "Jonathan", which appeared on the band's second album How To Meet Girls. British country rock band the Rockingbirds released the single "Jonathan, Jonathan" in tribute to Richman in 1992. The Silos also covered the Modern Lovers' "I'm Straight".

In 1993, he contributed the track "Hot Nights" to the AIDS-Benefit Album No Alternative produced by the Red Hot Organization.

Richman has continued his release schedule all along, with You Must Ask the Heart (1995), Surrender to Jonathan (1996), I'm So Confused (1998), Her Mystery Not of High Heels and Eye Shadow (2001), and Not So Much to Be Loved as to Love (2004). In 1998 a live album of Modern Lovers recordings from the early 1970s was released, Live at the Long Branch & More. There is also a DVD of a live performance, Take me to the Plaza (2002).

Another major profile boost was a key part in the Farrelly Brothers' 1998 film There's Something About Mary, where he played half of a two-man Greek chorus with Drummer Tommy Larkins, that commented on the plot while performing in the framed action itself. He also appeared briefly in a bar scene in a previous Farrelly Brothers film, Kingpin, and performed the song "As We Walk to Fenway Park" for their 2005 comedy, Fever Pitch.

A tribute album, If I Were a Richman: a Tribute to the Music of Jonathan Richman, was released by Wampus Multimedia in 2001.

In 2003, Richman married Nicole Montalbano of Chico, California. She contributed backing vocals to the album Not So Much to Be Loved as to Love (2004).

Rapper M.I.A. featured the opening lyrics from "Roadrunner" in the song "Bamboo Banga" on her 2007 album, Kala.

As a Producer himself, Richman and Drummer Tommy Larkins produced Vic Chesnutt's final album Skitter on Take-Off in 2009 which appeared on Vapor Records. Chesnutt opened for Richman at concerts many times during his later years.

Richman's minimalist songwriting style has been described as whimsical and childlike. He himself has stated, "I don’t write, really. I just make up songs."