He started his own recording career in March 1957, working with the A&R man and record producerJ. D. "Jay" Miller in Crowley, Louisiana. At his wife's suggestion, he took the name Slim Harpo in order to differentiate himself from another performer called Harmonica Slim. His first solo release, for Excello Records, based in Nashville, Tennessee, was "I'm a King Bee", backed with "I Got Love If You Want It" in 1957. The other musicians on the recording were Gabriel "Guitar Gable" Perrodin (guitar), John "Fats" Perrodin (bass), and Clarence "Jockey" Etienne (drums). Harpo played guitar in his live shows, but he usually used other guitarists when recording. The record was a regional hit but failed to make the national charts. He followed up with several more singles for Excello before having his first chart hit, "Rainin' in My Heart", in early 1961. The record reached number 17 on the BillboardR&B chart and number 34 on the U.S. pop chart, and it was followed soon after with an LP of the same name and additional singles. Many of his songs were co-written with his wife, Lovelle Moore, although she never received credit.
Never a full-time musician, Harpo had his own trucking business during the 1960s. According to writer Ryan Whirty, "Harpo and his band needed to tour constantly and play as much as possible; times were frequently lean financially, and the men had to scrape up whatever they could get." But, by 1964, several of his tracks had been released on albums and singles in the UK, and British rock bands like the Rolling Stones, the Pretty Things, the Yardbirds, the Kinks, Pink Floyd and Them began to feature versions of his songs in their early repertoires. The Moody Blues reportedly took their name from an instrumental track of Slim's called "Moody Blues".
Writer Cub Koda noted that: "Harpo was more adaptable than [Jimmy] Reed or most other bluesmen. His material not only made the national charts, but also proved to be quite adaptable for white artists on both sides of the Atlantic... A people-pleasing club entertainer, he certainly wasn't above working rock & roll rhythms into his music, along with hard-stressed, country & western vocal inflections... By the time his first single became a Southern jukebox favorite, his songs were being adapted and played by white musicians left and right. Here was good-time Saturday-night blues that could be sung by elements of the Caucasian persuasion with a straight face."
He had his biggest commercial success in 1966, when the predominantly instrumental "Baby Scratch My Back" reached no.1 on the R&B chart and no.16 on the US pop chart. Harpo described it as "an attempt at rock & roll for me." Like his previous records, it was recorded with producer J. D. Miller and the regular Excello musicians, including guitarist Rudy Richard, bassist James Johnson and drummer Jesse Kinchen, in Crowley, Louisiana. However, disagreements with Miller and a change in the record company's ownership led to two follow-ups, "Tip On In" and "Tee-Ni-Nee-Ni-Nu", being recorded in Nashville with new producer Robert Holmes. Both made the R&B charts. He recorded his 1968 album Tip On In in Nashville, using musicians Charles Hodges (organ), Mabon "Teenie" Hodges (guitar); Leroy Hodges (bass) and Howard Grimes (drums), who later became more widely known as the Hi Rhythm Section. He also recorded versions of Charlie Rich's "Mohair Sam" and Johnny Cash's "Folsom Prison Blues".
He recruited Lightnin' Slim to his touring band in 1968, and toured widely in the late 1960s, mainly reaching rock audiences. In January 1970, with his first scheduled tour of Europe and recording sessions planned, he died suddenly in Baton Rouge, of a heart attack, twenty days after his 46th birthday, despite being "one of the cleanest living bluesmen of his era". He was buried in Mulatto Bend Cemetery in Port Allen, Louisiana.
The Slim Harpo Music Awards, awarded annually in Baton Rouge, are named in his honour. Proceeds from the awards benefit the "Music in the Schools" outreach program.
2016 saw the release of Slim Harpo: Blues King Bee of Baton Rouge by UK blues scholar Martin Hawkins. David Fricke of Rolling Stone magazine described the work: ".. a passionate, encyclopedic triumph, bringing the enigmatic Harpo to life and tracing his remarkable mainstream ascension – from the rich central-Louisiana blues scene to gigs at the Fillmore East – with deep local research and detailed portraits of the singer's peers, sidemen and record-business associates."
1972 - The Excello Story (three tracks; various artists - Excello LPS-8025) 2LP
1976 - Slim Harpo...Knew The Blues (Vol. 2) (Excello/Nashboro 28030) 2LP/25 tracks compilation of LPS-8008, LPS-8013, and four singles: Excello 2301, 2305, 2306, 2309; plus one previously unreleased track: "Stick Your Chest Out Baby".
1978 - Slim Harpo...He Knew The Blues (Sonet SNTF-769) single LP/14 tracks sampler of Excello 28030.
1989 - Scratch My Back: The Best Of Slim Harpo (The Original King Bee) (Rhino #70169)
^Note: According to Louisiana music historian John Broven, his death was due to complications from a punctured lung. Notes to Slim Harpo, "The Excello Singles Anthology." Hip-O/Universal Music Enterprises, 2003.