Santo died in an Arizona hospital from complications of bladder cancer, according to WGN Radio.
Santo played for the Cubs from 1960-73 and wrapped up his career with the White Sox in 1974. He joined the Cubs' radio team in 1990.
A nine-time All-Star in his 15-year career, Santo batted .277 during his career, with a total of 2,254 career hits, 342 home runs and 1,331 RBIs.
He 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.
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 he shouted, "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."
"Ronnie will forever be the heart and soul of Cubs fans," Cubs Chairman Tom Ricketts said in a statement Friday. He praised Santo for "his passion, his loyalty, high great personal courage and his tremendous sense of humor."
Santo battled a myriad of serious medical problems after he retired as a player, having undergone surgery on his eyes, heart and bladder after doctors discovered cancer. On his legs alone, he underwent surgery more than a dozen times before they were ultimately amputated below the knees - the right one in 2001 and the left a year later.
Born Ronald Edward Santo in Seattle on Feb. 25, 1940, he was diagnosed with juvenile diabetes when he was 18. Santo kept his condition from the team until he made his first All-Star game in 1963, and fans didn't know about his diabetes for years after that.
"Nobody in 1959 when I was diagnosed at 18, nobody knew what diabetes was all about," Santo once told CBS Station WBBM. "There had never been a player in the Major Leagues that played a full career with juvenile diabetes."
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.
"If I hadn't had this when my troubles started, I don't know if I would have survived," he said in September 2003. "I really mean that. It's therapy."
His broadcast booth partner Pat Hughes told WBBM Friday morning that Santo loved the Cubs to the end, and kept his passion for his work regardless of his medical challenges.
Former Cubs President John McDonough told WBBM, "He was a tremendous guy. He had an amazing life. I feel like I've lost a partner and a good friend, and the Cubs have lost their No. 1 fan."
In Wrigleyville Friday morning, mourners were coming out before dawn.
"He was the face of the Chicago Cubs in my generation; I just found out," one man told WBBM. "We live one block from Wrigley; I've been to every home game for the last five years, and it's just sad."
Santo was a fan favorite on a team that included Hall of Famers Ernie Banks, Billy Williams and Ferguson Jenkins. Many taverns near Wrigley Field include photos of Santo, including one in which he famously clicked his heels as he ran off the field.
By all accounts it was a tremendous career. A five-time Gold Glove winner, Santo hit .300 or better four times; had the best on-base percentage in the league in 1964 and 1966; and led the league in walks four times.
But the Cubs routinely finished at or near the bottom of the standings.
One of the few times the Cubs didn't was in 1969, when they finished second after leading the New York Mets by nine games as late as Aug. 16. That year, a photograph was taken of Santo that became synonymous with both the team's failure and the supposed curses that have long haunted the team: There, in the on-deck circle at Shea Stadium, is Santo, a bat on his shoulder as a black cat scurries past.
Santo's disappointment with being passed over for induction into the Hall of Fame was well known to viewers, who watched him receive the news on the phone in 2003 thanks to television cameras he allowed inside his house when he thought he would be getting in.
In 2003, he was honored by the Cubs, who retired his No. 10, hoisting it up the left-field foul pole, just below Banks' No. 14.
"This flag hanging down the left-field line means more to me than the Hall of Fame," Santo told the cheering crowd at Wrigley Field when his number was retired.
"This couldn't be any better," he said. "With the adversity that I have been through if it wasn't for all of you, I wouldn't be standing here right now."
Santo had been active in fundraising for diabetes research, with his Walk-for-the-Cure raising millions of dollars.
Santo is survived by his wife, Vicki; their four children (Ron Jr., Jeff, Linda and Kelly) and two grandchildren.