In 1962, Kelley, then a practicing dentist in Texas, developed a disease involving body pains, weight loss, and depression. Using x-rays his doctor diagnosed pancreatic cancer and gave him only months to live and told that no treatment was available. Kelley then used diet and alternative medical methods as proposed by Max Gerson to "cure" his cancer. He then went on to formulate his cancer approach that included pancreatic enzymes, an individualized diet of vitamins, minerals, and other nutrients, and detoxification including coffee enemas. In 1971, the American Cancer Society added his regimen to a list of "unproven methods". In 1976 his dental license in Texas was revoked and he moved to Winthrop, Washington.

In 1980, his most famous patient, Steve McQueen, came to him in Winthrop, and after medical experts had given up on McQueen, in July 1980, Kelley's regimen was applied to McQueen in Mexico. Kelley became known as "McQueen's Holistic Medicine Man" (People Magazine) Although McQueen died (of cardiac arrest) only 3 months later, Kelley's regimen was sought out by many patients with terminal cancer.

In the 1970s, Kelley was tolerant in speaking about medical orthodoxy and looked forward to a fair and proper evaluation of his metabolic diet methods, which had become controversial, but he eventually became despondent that this could ever happen. He also became paranoid. He wrote a book entitled One Answer to Cancer detailing his experiences as well as his methods. By the 1980s, his marriage had broken up, he lost control of his once-thriving organization, and his mental and physical health deteriorated.

In the 1980s, New York physician Nicholas Gonzalez started to develop and investigate Kelley's methods further. A randomized phase III clinical trial for the possible treatment of pancreatic cancer with the Gonzalez Regimen was funded by a $1.4 million grant from the National Center for Complementary and Alternative Medicine, and co-sponsored by the National Cancer Institute, awarded in 1999 to Columbia University's Rosenthal Center for Alternative Medicine.Current clinical data are "limited and inconclusive" regarding the efficacy of this regimen as a treatment for cancer.

Kelley died of a heart attack, following readmittance to hospital, on January 30, 2005 in Arkansas City.