Menino, who served more than 20 years as mayor and presided over the city's highly lauded urban renewal, announced in March 2013 that he wouldn't run for a sixth term -- a decision that followed weeks of hospitalization for a respiratory infection and other health problems.
Two months after stepping down following the end of his final term in January, he announced that he was diagnosed with an advanced form of cancer that had spread to his liver and lymph nodes.
"Bold, big-hearted, and Boston strong, Tom was the embodiment of the city he loved and led for more than two decades," President Barack Obama said in a statement.
"As Boston's longest-serving mayor, Tom helped make his hometown the vibrant, welcoming, world-class place it is today. His legacy lives on in every neighborhood he helped revitalize, every school he helped turn around, and every community he helped make a safer, better place to live," Obama said.
Menino didn't seek re-election in January at the end of his fifth term. He had been mayor since 1993 and served as a city councilor before that.
'A great loss' to Boston
Boston Archbishop Cardinal Sean O'Malley Thursday called Menino a man "who placed family, faith and public service above all else."
"His passing is a great loss to the City of Boston, the Commonwealth, our country, and to his family, who were the center of his life," O'Malley said.
The archbishop said generations of Boston residents benefited from his "care and concern," first as a city councilor and later as mayor.
"Under Mayor Menino's leadership, the City of Boston achieved world class status while he always remained keenly focused on the needs and concerns of the city's neighborhoods and its people," O'Malley said in a statement.
In a statement, former New York Mayor Michael Bloomberg said Menino was "a terrific mayor and a close partner."
In 2006, Bloomberg said he and Menino formed Mayors Against Illegal Guns, a coalition that began as a meeting of 15 mayors and eventually grew to include more than 1,000 mayors from around the country.
"Whether it was tackling illegal guns or reviving neighborhoods, Tom was never afraid to take on tough issues," Bloomberg said. "He cared deeply about the people of Boston, and he was tireless in making his city a better place to live and work."
After the April 15, 2013, terror bombings at the Boston Marathon, which killed three people and wounded more than 260, Menino was "steady as always, showing the same determined leadership that made his career in public service one of Boston's most important and most influential," Bloomberg said.
Former presidential candidate and Massachusetts governor Mitt Romney wrote on Facebook, "Our hearts are heavy today with the loss of Tom Menino. Boston's giant passes on, but leaves behind a city grateful for his leadership and vision."
Cancer battle 'most profound challenge of his life'
In March, Menino disclosed his illness to the Boston Globe.
At the time, the former mayor began a chemotherapy regimen at the Dana-Farber Cancer Institute. He told the Globe that doctors ruled out surgery because he fell in the 3 or 4 % of cancer patients whose cancer can't be traced to an origin point within the body.
His battle with the disease, he said, was "the most profound challenge of his life."
"My attitude really is, we'll get through it," Menino told the paper. "We got through the (illnesses in 2012), we'll get through this. I have great doctors and supportive friends."
"What else can you do," he said. "What I don't want is people feeling sorry for me. I don't want sympathy. There are people worse off than me. It's my biggest concern -- I don't want to be treated any differently."
The diagnosis took him completely by surprise, Menino said, but he was no stranger to medical hardship.
During his tenure, he was hospitalized numerous times: for kidney stones in 1995 and 1997, for surgery to remove a tumor on his back in 2003, and when he was diagnosed with Crohn's disease in 2004.
In late 2012, the mayor spent eight weeks in Boston hospitals after he fell ill on a European vacation. During his hospitalization, he was diagnosed with a respiratory infection, a blood clot, a cracked vertebra and Type 2 diabetes.
Menino and his wife, the former Angela Faletra, had two children, Susan Fenton and Thomas M. Menino Jr.