A Florida Highway Patrol crash report said the former wrestler - whose legal name was Randy Mario Poffo - was driving a Jeep Wrangler when he lost control in Pinellas County around 9:25 a.m. The Jeep veered over the raised concrete median divider, crossed over the eastbound lanes and collided head-on with a tree.
Police said he may have suffered a "medical event" before the accident, but the report did not elaborate, and it said officials would need to perform an autopsy to know for sure.
The report said a woman in the vehicle, identified as Barbara Poffo, suffered minor injuries. A statement from Stamford, Conn.-based World Wrestling Entertainment said the passenger was the wrestler's wife.
"Poffo will be greatly missed by WWE and his fans," the statement said.
Savage was a charismatic wrestler made famous for his "Macho Man" nickname and his "Oooh Yeah!" catchphrase. He was a champion in Vince McMahon's World Wrestling Federation, and later Ted Turner's now-defunct World Championship Wrestling.
Poffo was under contract with WWE from 1985 to 1993 and held both the WWE and Intercontinental Championships.
"Our sincerest condolences go out to his family and friends. We wish a speedy recovery to his wife Lynn," WWE said.
Savage defined the larger-than-life personalities of the 1980s World Wrestling Federation (now WWE). He wore sequined robes bejeweled with "Macho Man" on the back, rainbow colored cowboy hats and oversized sunglasses, part of a unique look that helped build the WWF into a mainstream phenomenon.
For most of his career, his valet, Miss Elizabeth, was by his side. Elizabeth Hulette was his real-life wife. They later divorced, and Hulette died in 2003 - one of the many performers in the sport to die young.
The WWF made Savage their champion after a win over Ted DiBiase in the main event at WrestleMania in 1988.
Savage had not appeared for a major wrestling organization since 2004 when he performed for Total Nonstop Action.
He was both at times the most popular and most hated wrestler in entertainment. His flying elbow off the top rope was mimicked by basement and backyard wrestlers everywhere. Savage made good use of his deep, raspy voice as a corporate pitchman as well, for years ordering Slim Jim fans to "Snap into it!"
He's most known his legendary rivalries with Hulk Hogan, Ricky Steamboat and Ric Flair. Wrestlers took to Twitter to let fans know Savage won't be forgotten.
Dwayne "The Rock" Johnson hailed Savage as one of his childhood inspirations and heroes, while Mick "Cactus Jack" Foley called Savage "one of my favorite performers."
Hogan said he and Savage had just started talking again after 10 years.
"He had so much life in his eyes and in his spirit, I just pray that he's happy and in a better place and we miss him," Hogan wrote.