Gwynn had been on medical leave from his head coach position at San Diego State since March and had signed a one-year extension on Wednesday.
"Mr. Padre" won a record eight National League batting titles -- equal to the number won by Honus Wagner -- and collected 3,141 hits in his career, 19th all time. He was inducted into the Hall of Fame in 2007 along with Orioles great Cal Ripken in front of an estimated 75,000 people in Cooperstown, N.Y.
"Major League Baseball today mourns the tragic loss of Tony Gwynn, the greatest Padre ever and one of the most accomplished hitters that our game has ever known, whose all-around excellence on the field was surpassed by his exuberant personality and genial disposition in life," Commissioner Bud Selig said in a statement. "Tony was synonymous with San Diego Padres baseball, and with his .338 career batting average and eight batting titles, he led his beloved ballclub to its greatest heights, including two National League pennants.
"Tony loved our game, the city of San Diego and his alma mater where he starred and coached, San Diego State University, and he was a part of a wonderful baseball family. His commitment to the children of San Diego made him a deserving recipient of our game's highest off-field honor, the Roberto Clemente Award, in 1999.
"For more than 30 years, Tony Gwynn was a source of universal goodwill in the national pastime, and he will be deeply missed by the many people he touched. On behalf of all of our clubs, I extend my deepest condolences to Tony's wife Alicia, their son Tony Jr. of the Phillies, their daughter Anisha, the Padres franchise, his fans in San Diego and his many admirers throughout Baseball."
Gwynn's battle with cancer began in 2009 when a malignant tumor was removed from his right cheek. Gwynn claimed that the cancer in the salivary gland was the result of his longtime habit of chewing tobacco. The cancer returned twice, and in the latter part of '12, he again began radiation treatment in an attempt to shrink the tumor.
Gwynn underwent another round of surgery in early 2012 when the nerve that the tumor was wrapped around had to be replaced with one from his shoulder. In each case, Gwynn valiantly fought back.
"The whole experience was traumatic, because I thought I had it beat, and dang, it came back," Gwynn said during a visit to the Hall of Fame later that year for the induction ceremony. "I can't say enough how fortunate I feel to be here after 14 hours of surgery. I remember waking up and just smiling and laughing, because I wasn't sure I was going to wake up. Everything after that's a plus. That's how I'm looking at it. We've always tried to attack it positively, and that's what we did this time. Hopefully I'll beat it, but we'll see."
Gwynn's career-high .394 average during the strike-shortened 1994 season remains the highest to lead either league since Williams batted .406 in 1941. Gwynn always believed had it not been for the strike, which ended the season in mid-August, he would have hit .400.
Gwynn won his first batting title in 1984, his first full big league season, with a .351 average. He won three straight batting crowns from 1987-89 and four straight from 1994-97. His .370 average in 1997 was the highest in the NL (for a full season) since Stan Musial's .376 in 1948. The only year Gwynn did not reach the .300 mark was 1982, his rookie season, when he played in 54 games. He stole 319 bases, including 56 in '87 and 40 in '89. He averaged 22 strikeouts a year. He is the Padres' career leader in virtually every offensive category.
"People in San Diego are never going to see anybody like that again," said John Moores, the Padres' former majority owner from 1995-2012. "It's impossible. It will never happen. Not in 10 lifetimes. He was a special player, but it's more than that. It was the dedication. He just did what he wanted to do. That was the way he lived. Whether right or wrong he did it on his own terms. He wasn't interested in the money. He wanted to stay in San Diego. He wanted to live a certain way and he did."
Gwynn played for the 1984 and '98 pennant-winning Padres and considered his home run at Yankee Stadium in Game 1 of the 1998 World Series to be one of the highlights of his stellar career. He hit .371 in nine World Series games and .306 in 27 postseason games.
Gwynn laced his 3,000th hit -- a patented single -- at Montreal's Olympic Stadium on Aug. 6, 1999, his mother's birthday. He got his 2,000th hit on the same date in 1993. He reached 3,000 hits in his 2,284th game, the third fewest needed to reach the mark, behind just Ty Cobb (2,135) and Nap Lajoie (2,224).
"I am deeply saddened to learn that Tony Gwynn has lost his courageous battle against cancer," MLBPA executive director Tony Clark said. "Since his diagnosis, Tony displayed the same tenacity and drive in his fight against this horrible disease that he brought to the plate in every at bat of his Hall of Fame career. Growing up in San Diego, I was inspired by Tony's passion for excellence, and I was honored to have played against him as a Major Leaguer. Our thoughts and prayers go out to his wife, Alicia, his daughter, Anisha, his son and fellow Major Leaguer, Tony, Jr., and his many friends and fans. Tony will be missed."
A left-handed hitter from Los Angeles who grew up in nearby Long Beach, Calif., Gwynn collected 2,378 singles. Gwynn was so proficient at hitting the ball into left field between third base and shortstop that people called the slot the "5.5 Hole" in his honor. For most of his career, Gwynn wore those figures embossed on the tongue of his baseball shoes. He was a 15-time NL All-Star and won five Gold Gloves for his defensive play in right field.
Gwynn hit 135 homers and knocked in 1,138 runs in 2,440 games, both stats he considered to be personal shortcomings. He also never reached 150 games in a season after 1989 because of incessant knee and leg injuries. Gwynn thought his lack of power might affect his election to the hallowed Hall.
Instead, Gwynn and Ripken were elected together in their first year on the ballot with two of the highest vote totals in history. Ripken garnered 98.53 percent of the vote from the Baseball Writers' Association of America, the most ever for a position player. Gwynn's percentage of 97.6, 13 of 545 votes short of unanimous, ranked seventh directly behind Cobb, George Brett and Hank Aaron -- pretty good company. A record 53 Hall of Famers attended the induction.
"I thought I was going to get penalized," Gwynn said. "I didn't win any [World Series] championships. I didn't hit a whole lot of home runs. I didn't drive in a whole lot of people. To be one of those lucky ones to get in is a blessing."
Gwynn is survived by his son, Tony Jr., an outfielder who has played parts of eight seasons in the big leagues; his wife, Alicia; his daughter, Anisha, a rhythm-and-blues artist; and four grandchildren. Tony Sr.'s brother Chris, also an outfielder, played parts of 10 seasons in the Majors, seven of them with the Dodgers. Tony Sr. and Chris were teammates on the NL West-champion Padres in 1996.
Tony Jr. tweeted the following on Monday: "Today I lost my Dad, my best friend and my mentor. I'm gonna miss u so much pops. I'm gonna do everything in my power to continue to make u proud!"
The Padres erected a statue of Gwynn at Petco Park in 2007. The address of the team's home ballpark is 19 Tony Gwynn Drive.