Spokeswoman Dot Joyce said in a statement that Menino died in the company of his family and friends.
Menino was first elected in 1993 and built a formidable political machine that ended decades of Irish domination of city politics, at least temporarily. He won re-election four times. He was the city's first Italian-American mayor and served in the office for more than 20 years before a series of health problems forced him, reluctantly, to eschew a bid for a sixth term.
"I can run, I can win and I can lead, but not in the neighborhoods all the time as I like," Menino, a Democrat, told an overflow crowd at Boston's historic Faneuil Hall on March 28, 2013.
Less than three weeks after that announcement, two bombs exploded at the finish line of the Boston Marathon, killing three people and injuring more than 260. Menino, who had undergone surgery on a broken leg just two days earlier, checked himself out of a hospital to help lead his shaken city through the crisis.
At an interfaith service three days after the bombings, Menino, in a symbolic act of personal defiance, painfully pulled himself to his feet from his wheelchair to declare that no act of violence could break Boston's spirit.
He was in an SUV in nearby Watertown at the end of a daylong manhunt when Police Commissioner Edward Davis informed him that the surviving bombing suspect had been captured. Menino's tweet: "We got him."
Menino was anything but a smooth public speaker and was prone to verbal gaffes. He was widely quoted describing Boston's notorious parking shortage as "an Alcatraz" around his neck, rather than an albatross.
He often mangled or mixed up the names of Boston sports heroes — once famously confusing former New England Patriots kicker and Super Bowl hero Adam Vinatieri with ex-Red Sox catcher Jason Varitek. But while such mistakes might sink other politicians in a sports-crazed city, they only seemed to reinforce his affable personality and ability to connect with the residents he served.
"I'm Tom Menino. I'm not a fancy talker, but I get things done," he said in his first TV ad.
In an interview with The Associated Press in March, Menino said he "loved every minute" of being mayor, even during the city's darkest days. He credited his staff and others, downplaying his own role.
"I just did my job — nothing special," he said.
There has already been reaction from the Massachusetts congressional delegation, national party leaders, and other state officials.
US Sen. Elizabeth Warren: "The City of Boston lost a great fighter today. Mayor Tom Menino used his big heart, his strong voice, and his fierce determination to shape every corner of the city. Bruce and I send our prayers to Mayor Menino's wife Angela, to his family, and to all Bostonians. Our mayor is gone, but he lives on in every neighborhood in Boston."
Former Boston mayor, ex-Vatican ambassador Raymond Flynn: "Boston is a better city because of Tom Menino and the people of Boston are grateful for his commitment and service. ... The day I left City Hall to become U.S. Ambassador to the Vatican, I said, "The City is in good hands." ''Today, Tom Menino is in good hands."
DNC Chair Rep. Debbie Wasserman Schultz: "There are few figures so intimately connected with their hometown as were Tom Menino and Boston. He loved the city and its people, and devoted his life to them; for that, they loved him back."
State Attorney General Martha Coakley: "Today, Boston has lost the greatest mayor in its history. He was a friend and mentor, and a shining example to me and countless others of what it means to love and serve your community."
State Senate President Therese Murray: "No one will ever love Boston as much as Tom Menino did. I will dearly miss his friendship and, while we will always mourn his loss, Mayor Menino will live through Boston forever."
Boston University President Robert A. Brown: "Boston has lost one of its greats. Because Tom Menino worked so hard to make Boston a welcoming, vibrant, safe place to live and work, Boston University – located in the heart of the city – has benefited immensely."
Thomas Michael Menino was born on Dec. 27, 1942, in the city's Hyde Park neighborhood. A former insurance salesman, he caught the political bug while working as a legislative aide to state Sen. Joseph Timilty. He first earned elective office as a district city councilor in 1984.
Menino became the council's president in 1993 and was automatically elevated to mayor when then-mayor Raymond Flynn was named U.S. ambassador to the Vatican. While that prompted some to initially chide Menino as an "accidental mayor," he quickly proved his own political mettle, winning a four-year term later that year.
He never sought nor showed interest in running for higher office. Mayor, it seemed, was the only political job to which he aspired.
Menino's health was often a concern, and he was admitted to the hospital several times while in office.
In 2003, he underwent surgery to remove a rare sarcoma on his back. The following year, his doctors confirmed he has been diagnosed with Crohn's disease, a type of inflammatory bowel disease.
He spent six weeks in the hospital in 2012 for a series of ailments, including a respiratory infection. While he was in the hospital, he suffered a compression fracture in his spine and was diagnosed with Type 2 diabetes.
In May 2013, he was back in the hospital for surgery for an enlarged prostate. In typical fashion, he declared on his release several days later that he would not let the latest ailment slow him down.
"I'm raring to go," he said.
Menino left City Hall on his final day in office Jan. 6 to thunderous applause from city workers. Later, he tweeted: "Thank you Boston. It has been the honor and thrill of a lifetime to be your Mayor. Be as good to each other as you have been to me."
In March 2014, Menino revealed in an interview with The Boston Globe he was battling an advanced form of cancer that had spread to his liver and lymph nodes. Doctors said they were unable to pinpoint where the cancer originated.
In a statement announcing he was stopping treatment to devote himself to his loved ones, Menino said he was "hopeful and optimistic that one day the talented researchers, doctors and medical professionals in this city will find a cure for this awful disease."
Menino leaves behind his wife Angela, his children Susan and Thomas Jr., a Boston police officer, and six grandchildren.