The third baseman turned broadcaster died from complications from bladder cancer. He lapsed into a coma on Wednesday and died Thursday.
The former Cub battled health issues all his life. He overcame several injuries related to his diabetes, including the amputation of both his legs.
Cubs president Tom Ricketts said it was an honor to know the baseball icon.
"Ronnie will forever be the heart and soul of Cubs fans," Ricketts said in a statement. "Our thoughts and prayers today are with his wife Vicki and their family and we share with fans across the globe in mourning the loss of our team’s number one fan and one of the greatest third basemen to ever play the game."
Santo was a nine-time all-star in his 15-year career as Cubs third baseman and hit .277 with 365 doubles, 67 triples, 342 home runs, 1,331 RBI and 1,138 runs in 2,243 games covering 15 major league seasons with the Cubs (1960-73) and White Sox (1974), according to a team release.
The cheery broadcaster was widely regarded as one of the best players never to gain induction into the Hall of Fame. The quiet sadness with which he met the news year after year that he hadn't been inducted helped cement his relationship with the fans.
"I could never wrap my brain around why Santo wasn't inducted into the hall of fame," said pitcher Ryan Dempster in telephon conversation with NBC Chicago. "Not just for what he did as a player all those years, playing with diabetes, but as a broadcaster too. ... I think his numbers alone are good enough. It's too bad he never got to see himself go into the hall."
But nothing brought fans closer to Santo -- or caused critics to roll their eyes more -- than his work in the radio booth, where he made it clear that nobody rooted harder for the Cubs and nobody took it harder when they lost. Santo's groans of "Oh, nooo!" and "It's bad" when something bad happened to the Cubs, sometimes just minutes after shouting, "YES! YES!" or "ALL RIGHT!" became part of team lore as the "Cubbies" came up short year after year.
"The emotion for me is strictly the love I have for this team," Santo told The Associated Press in August 2009. "I want them to win so bad."
Santo began broadcasting games on WGN radio in 1990. Even though the Cubs failed to make the World Series in his lifetime, Santo once said his association with the team probably prolonged his life.