O'Keeffe was born in Ripley, Tennessee. A star football athlete, he attended the United States Air Force Academy and played halfback on the freshman football team in 1972. However, in 1973 he transferred to Mississippi State University under a football scholarship, playing as an offensive lineman. During this time, he bulked up to 240 lb (110 kg). Subsequently, he transferred to University of the South in Sewanee, Tennessee and became a small college All-American playing both tight end and linebacker.
After studying political science and psychology, O'Keeffe became a prison counselor in the Tennessee penal system for a year or two where he became manager of playground activities and inmate weightlifting programs. He left for California to play in a semi-professional rugby team before becoming involved with Hollywood.
Although O'Keeffe is known for his big break as Tarzan, he is also remembered for his performances in the title role of the first three Ator sword and sorcery films produced in Europe in the 1980s. The series gained attention in 1991 after a re-edited version of the second installment, released as Cave Dwellers, was lampooned on the television series Mystery Science Theater 3000 (MST3K). The episode, which soon became immensely popular among fans, included one of the most-quoted quips in the show's history: "How much Keeffe is in this movie anyway?" "Miles O'Keeffe!" Unlike some of MST3K's subjects (such as Sandy Frank), O'Keeffe is considered to be a "good sport" and is a fan of the series. He enjoyed the MST3K treatment of the film so much that he requested a copy of the episode.

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