Over his decades-long career, the trombonist, composer, arranger and singer produced more than 40 albums that sold more than 30 million copies worldwide.
He collaborated with a wide range of artists, including the Fania All Stars, David Byrne and Celia Cruz.
His celebrated collaboration with Rubén Blades, Siembra, became one of the bestselling salsa albums of all time, and the pair were known for addressing social issues through the genre.
Colón's family and manager confirmed his death through social media posts.
"Willie didn't just change salsa; he expanded it, politicized it, clothed it in urban chronicles, and took it to stages where it hadn't been heard before," manager Pietro Carlos wrote.
"His trombone was the voice of the people, an echo of the Caribbean in New York, a bridge between two cultures."
Colón, who was nominated for 10 Grammys and one Latin Grammy, made famous songs such as El gran varón, Sin poderte hablar, Casanova, Amor verdad and Oh, qué será.
Blades said on X he was "reluctant to believe" his collaborator had died and offered his condolences to Colón's family.
Born in New York's Bronx borough, Colón was raised by his grandmother and aunt, who from a young age nurtured him with traditional Puerto Rican music and the typical rhythms of the Latin American repertoire, including Cuban son and tango.
At 11 he ventured into the world of music, first with flute, then bugle, trumpet and finally trombone, with which he stood out in the then-nascent genre of salsa.
His interest in trombone arose after hearing Barry Rogers playing it on Dolores, Mon Rivera's song with Joe Cotto.
"It sounded like an elephant, a lion ... an animal. Something so different that, as soon as I heard it, I said to myself: 'I want to play that instrument,'" he recalled in an interview published in the Colombian newspaper El Tiempo in 2011.
At 17 he joined the group of artists that formed the famous record label Fania Records, led and created by Jerry Masucci and Johnny Pacheco.
Fania was largely responsible for the new sound that was produced in the Latin world of New York and would later be called "salsa".
Colón's main characteristic as a musician was the fusion of rhythms, as he harmonised jazz, rock, funk, soul and R&B with the old Latin school of Cuban son, cha-cha-cha, mambo and guaracha, adding the nostalgia of the traditional Puerto Rican sound that encompasses jíbara, bomba and plena music.
In 2004 the Latin Recording Academy awarded Colón a special Grammy for his career and contributions to music.
As a community leader, Colón fought for civil rights.
He was part of the Hispanic Arts Association, the Latino Commission on AIDS, the Arthur Schomburg Coalition for a Better New York and the Congressional Hispanic Caucus Institute, among others.
In 1991 he was honoured with the Chubb fellowship from Yale University, a public service recognition also awarded to the likes of John F Kennedy, Moshe Dayan, the Reverend Jesse Jackson and Ronald Reagan, among others.
He served as special assistant to David Dinkins, New York's first Black mayor and was later appointed special assistant and adviser to Mayor Michael Bloomberg.
Colón had little luck running for public office himself, however.
He failed in a challenge to Eliot Engel in the 1994 Democratic primary, and in 2001 came in third in the Democratic primary for New York's public advocate.
He backed Hillary Clinton's presidential campaign in 2008, but he told the Observer he voted for Donald Trump in 2016.
His friendship with Blades ruptured after Colón sued for breach of contract over the 2003 concert Siembra ... 25 years later, held in Puerto Rico.
He also sparked a controversy when he called the then-president of Venezuela, Hugo Chávez, "rotten".
Colón acted in films such as Vigilante, The Last Fight and It Could Happen to You, and on TV in Miami Vice and Demasiado Corazón.
More recently he appeared in Bad Bunny's music video for NuevaYol.
He is survived by his wife and four sons.
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