Holliday, a product of the Copiague area of Long Island, New York was raised in a Christian home, born into a Baptist family. At age 12 he lost his father. With the encouragement of his mother he participated in track at Copiague High School where he was part of the Fantastic Four Relay Team and was the star of his football team. He was nicknamed as Mr. Hotshot and was known as a "scoring machine" on the football field. He graduated in 1967 and attended University of Maryland on a full scholarship. As he recalled, times were turbulent and the football team was preparing to go on strike against the NCAA over a change in coaches.

He was "jazzed" by a class he took related to the history of theater and acting became his new passion. In 1969, as an undergraduate he played Yank in The Hairy Ape by Eugene O'Neill. He was the first black person to perform in a leading role on the college's "main stage."

After graduation from college his first work was with the Inaugural Theater Group at the Folger Shakespeare Library in Washington, D.C. There, he conducted workshops as a founding member of the D.C. Black Repertory Company. In 1975, he was fired from his job because of his continued problems with drugs and alcohol. His chemical abuse continued for the next 14 years. However, despite those problems he starred in the role of Carlyle in David Rabe's Vietnam War-era play Streamers at the Lincoln Theatre.

That play led him to Los Angeles in 1976 where he guest-starred on several shows such as: Kojak, What's Happening!!, The Incredible Hulk, Quincy, M.E., Lou Grant, Soap, its spin-off series, Benson, The Jeffersons, The Fall Guy, Hart to Hart, and Doogie Howser, M.D. He guest starred on many other shows, also. His first "featuring" television series was Carter Country where he co-starred with Victor French as Sgt. Curtis Baker from 1977 until 1979. He also was featured in Roots: The Next Generations and starred in a series of pilots which failed to make it to the air as regular series. Kene provided the voice of the character Roadblock in the 1980s cartoon series, G.I. Joe and 1987's G.I. Joe: The Movie. In 1985, he appeared in the TV film Badge of the Assassin.

In early 1986, while providing the voice of Roadblock, he received a phone call from producers Fred Silverman and Dean Hargrove. He was their first choice to play Matlock's private investigator Tyler Hudson on the Matlock series. He would play opposite TV veteran Andy Griffith who was Matlock. Holliday said in a 2012 interview with Blake Radio, when Holliday was an 11-year-old boy, he had occasionally watched The Andy Griffith Show, who had recognized all the characters from his mentor's show, had won the role. He was eventually fired from the series due to ongoing concerns around his substance abuse.

He has numerous television and movie appearances to his credit, including roles in G.I. Joe: The Movie (1987), CBS’s made-for-television movie Miracle On The Mountain (2000), Hope & Faith (2004), and Law & Order: Special Victims Unit (2005).

He published a book of poetry in 1998 entitled The Book of K-III: The Contemporary Poetics of Kene Holliday.

While taking care of his mother, he accepted the lead role in the movie Great World of Sound, in 2007.