By the age of seven, Ronald was singing onstage at venues such as the Regal Theater in Chicago, alongside Dinah Washington and a few other notables. By his early teens, he was singing regularly with his brothers in church tours.
As a preteen Ronald joined siblings Rudolph, O'Kelly, and Vernon to form the earliest incarnation of the group. After Vernon's 1955 death in a bicycling accident, Ronald was tapped as the remaining trio's lead vocalist.
In 1957, sixteen-year-old Ronald and his two elder brothers Kelly, 19 and Rudy, 18, moved to New York recording doo-wop for local labels before landing a major deal with RCA Records in 1959, where the trio wrote and released their anthemic "Shout."
Only after the Isleys left RCA for the Wand label did they have another hit, this time with their seminal 1962 cover of the Top Notes' "Twist and Shout."
For much of the Isley Brothers' long career, Ron Isley would remain the group's consistent member of the group as well as the lead vocalist for most of the group's tenure - with occasional lead sharing with his brothers. In 1969, Ron and his brothers reformed T-Neck Records in a need to produce themselves without the control of record labels, forming the label shortly after ending a brief departure with Motown.
In 1973, the group's style and sound drastically changed following the release of the 3 + 3 album where brothers Ernie Isley and Marvin Isley and in-law Chris Jasper entered the group, writing the music and lyrics to the group's new sound. The younger brothers had been providing instrumental help for the brothers since the late 1960s.
After Kelly Isley's death in 1986 and Rudy Isley's exit to fulfill a dream of ministry in 1989, Ronald has carried on with the Isley Brothers name either as a solo artist or with accompanying help from the group's younger brothers, much more prominently, Ernie Isley.
In 1990, Ronald Isley scored a top ten duet with Rod Stewart with a cover of his brothers' hit, "This Old Heart of Mine (Is Weak for You)" and in 2003, Ronald recorded a solo album, Here I Am: Bacharach Meets Isley, with Burt Bacharach. In addition, Ron Isley became a sought-after hook singer for hip-hop acts such as R. Kelly, Warren G., 2Pac and UGK.
Ronald released his first solo album Mr. I on November 30, 2010. The album includes the first single "No More." It debuted at #50 on The Billboard 200 selling 22,243 copies. It was his first solo album to crack that chart.
In 2010, Isley received a "Legend Award," surveying Isley Brother music written largely by the younger brothers, at the Soul Train Music Awards.
In 2004, while in London, Isley suffered a mild stroke, which halted an Isley Brothers tour. Then, in September 2005 Isley made headlines by marrying background singer, Kandy Johnson of the JS/Johnson Sisters; Johnson was 28 and Isley 63. Their son Ron Jr. was born in January 2007.
In 2007, it was reported Isley had kidney problems and lived with a pacemaker.