Wheeler was born and raised in Fresno, California. He grew up in poverty. As a child, Wheeler experienced child abuse and suicidal tendencies. He struggled in school due to dyslexia, but excelled in sports. Wheeler began training in martial arts, and started bodybuilding as a teenager after discovering weight training. He is on record as regarding himself as a "martial artist first, a bodybuilder second." Wheeler has remarkable flexibility, including being able to do a complete split, which led to his nickname.
After a short career as a police officer, Wheeler focused full-time on becoming a professional bodybuilder. He competed for the first time in 1983, but it was not until 1989 that he secured a first-place trophy at the NPC Mr. California Championships. He placed second at the 1993 Mr. Olympia, narrowly missing a win (something he was to repeat in 1998 and 1999). He is a 5-time Ironman Pro winner, 4-time Arnold Classic winner, and has won the France Grand Prix, South Beach Pro Invitational, Night of Champions, and Hungarian Grand Prix.
While Wheeler had the reputation of being arrogant and overconfident, he attributed this to a need to compensate for his introversion and insecurity as a child and young man. In 1994, he was involved in a near-fatal car accident that could have left him with lifelong paralysis. Falling back into depression again, he started training from scratch, returning with remarkable speed to bodybuilding's top tier. In 1999, Wheeler discovered that he had focal segmental glomerulosclerosis, a form of kidney disease. Despite press speculation as to the cause of the failure, Wheeler pointed out that the condition is hereditary, although drug use probably accelerated its onset. Wheeler announced his retirement from competitive bodybuilding in 2000, but continued to compete until 2003.
Flex made a comeback at the 2017 Mr. Olympia, competing in the Classic Physique division, and finished at 15th place.
After retirement, Wheeler focused again on martial arts, his favorite being Kenp-Kwon-Do, a variant of Kenpo, Tae Kwon Do, and Aikido. In 2003, he received a kidney transplant; he then went on to participate in a demonstration fight at the 2005 Arnold Classic. In 2007, Flex was interviewed by freelance journalist Rod Labbe for Ironman Magazine's Legends of Bodybuilding series. Entitled "Yesterday and Today," it covers his extensive career and reveals how people can conquer adversity and triumph against incredible odds. Wheeler served in an executive position as the Director of Media and Public Relations for the sports nutrition company All American EFX, based out of Bakersfield, California. He also managed their sponsored athletes and can be seen in advertisements for the company.
In October 2019, Flex underwent amputation of his right leg below the knee due to circulatory vascular system problems. Wheeler said the decision to amputate was "due to escalating circulation difficulties in my right leg that had become life threatening."
Some medical professionals assert that what led to the need for Wheeler's lower leg amputation was an accumulation of pre-existing medical conditions involving the Focal segmental glomerulosclerosis he acquired hereditarily, leg injuries he received in his martial arts training, his car crash in 1994, and his kidney transplant in 2003, which together long-term resulted in the circulation issues.