In his teenage years, Isaacs became a veteran of the talent contests that regularly took place in Jamaica. In 1968, he made his recording debut as Winston Sinclair, with the single “Another Heartache”, recorded for producer Byron Lee.The single sold poorly and Isaacs went on to team up with Errol Dunkley to start the African Museum record label and shop, and soon had a massive hit with “My Only Lover”, credited as the first lovers rock record ever made. He recorded for other producers to finance further African Museum recordings, having a string of hits in the three years that followed, ranging from ballads to roots reggae, including “All I Have Is Love”, “Lonely Soldier”, “Black a Kill Black”, “Extra Classic” and his cover version of Dobby Dobson’s “Loving Pauper”. In 1974, he began working with producer Alvin Ranglin, and that year he had his first Jamaican no. 1 single with “Love Is Overdue”.

Isaacs recorded for many of Jamaica’s top producers during the 1970s, including Winston “Niney” Holness, Gussie Clarke (“My Time”), Lloyd Campbell(“Slavemaster”), Glen Brown (“One One Cocoa Fill Basket”), Harry Mudie, Roy Cousins, Sydney Crooks and Lee “Scratch” Perry (“Mr. Cop”). By the late-1970s, Isaacs was one of the biggest reggae performers in the world, regularly touring the US and the UK, and only challenged by Dennis Brown and Bob Marley.Between 1977 and 1978, Isaacs again teamed up with Alvin Ranglin, recording a string of hits including “Border” and “Number One” for Ranglin’s GG’s label.

He opened the Cash and Carry shop at 118 Orange Street, later moving to no. 125, next door to Prince Buster’s Record Shack, which was also the base for the Cash and Carry record label that he ran with Trevor “Leggo” Douglas.International stardom seemed assured in 1978 when Isaacs signed to the Virgin Records offshoot Front Line Records, and appeared in the film Rockers, in which he performed “Slavemaster”. The Cool Ruler (which became one of his nicknames) and Soon Forward albums, however, failed to sell as well as expected, although they are now considered among his best work. In 1981, he made his first appearance at the Reggae Sunsplash festival (returning annually until 1991), and he moved on to the Charisma Records offshoot Pre, who released his The Lonely Lover (another nickname that stuck) and More Gregoryalbums along with a string of increasingly successful singles including “Tune In”, “Permanent Lover”, “Wailing Rudy” and “Tribute to Waddy”. He signed to Island Records and released the record that finally saw him break through to a wider audience, “Night Nurse”, the title track from his first album for the label (Night Nurse (1982)). Although “Night Nurse” was not a chart hit in either the UK or US, it was hugely popular in clubs and received heavy radio play, and the album reached number 32 in the UK.This success for Isaacs coincided with drug problems with cocaine that saw him serve a six-month prison sentence in Kingston in 1982 for possession of unlicensed firearms. Isaacs claimed that he had the weapons only for protection, but it emerged that this was his 27th arrest and that he had become involved in drug dealing and was addicted to crack cocaine. He celebrated his release from prison with his second album for Island, Out Deh! (1983). He was featured in the 1982 documentary Land of Look Behind.

In 2010, Gregory Isaacs put out the last of his albums to be released while he was still living; Isaacs Meets Isaac, with Zimbabwean reggae singer King Isaac. In November 2010, Isaacs Meets Isaac was nominated for Best Reggae Album for the 2011 Grammy Awards, giving Gregory Isaacs his fourth Grammy nomination, and Zimbabwe’s King Isaac his first.