The three-time Grammy Award winner had been fighting throat cancer since 1998.
"Levon Helm passed peacefully this afternoon," Helm's manager Barbara O'Brien said in a statement.
"He was surrounded by family, friends and band mates and will be remembered by all he touched as a brilliant musician and a beautiful soul."
Tributes immediately began pouring in from fans, popping up on Twitter at a fast rate.
Although the cancer silenced Helm's crystal-clear tenor for a while, he strengthened his voice sufficiently to resume singing in 2004. He hosted a regular series of what he called "Midnight Ramble" concerts that often featured big-name stars at his home-studio in Woodstock, New York.
In addition to singing, Helm played drums, mandolin and other string instruments in The Band, one of the most revered and influential rock groups to emerge from the 1960s. Inducted into the Rock and Roll Hall of Fame in 1994, it played a brand of rustic rock that drew on country, blues and rhythm and blues and sounded quintessentially American - even though Helm was the only member not from Canada.
Helm's daughter Amy, who sang in his latest band, and wife, Sandy, announced on Tuesday the he was in the final stage of his fight with cancer.
"Thank you fans and music lovers who have made his life so filled with joy and celebration," they said on Facebook. "He has loved nothing more than to play, to fill the room up with music, lay down the back beat, and make the people dance! He did it every time he took the stage.
BACKED UP DYLAN
Helm was born to cotton farmers in 1940 and grew up near the community of Turkey Scratch, outside Helena, Arkansas, with the intention of being a musician. He was a teenager when he became the drummer for another Arkansas native, rockabilly singer Ronnie Hawkins.
Hawkins took the group to Canada, where he added guitarist Robbie Robertson, bassist Rick Danko and keyboardists Richard Manuel and Garth Hudson to The Hawks. Eventually the four Canadians and Helm would split off.
In 1965, Bob Dylan recruited them to back him up on his first U.S. "electric" tour, a raucous event strung over September 1965 to May 1966 that marked Dylan's transition from acoustic to rock 'n' roll and outraged his folkie fans.
Helm was dismayed by the hostile reception and returned to Arkansas for a two-year hiatus. Eventually reunited with his bandmates in 1968 and calling themselves simply The Band, they produced the landmark "Music From Big Pink," an album named for the house they rented near Woodstock.
That was followed the next year by the "brown album" titled The Band. Viewed by most critics as their masterpiece, the album was steeped in old-time rural Americana and made heavy use of Helm's plaintive Southern drawl.
The Band's greatest success came in the early and mid-1970s and, while they were not a huge commercial success, critics loved them. "Up on Cripple Creek," "The Weight" and the Civil War saga "The Night They Drove Old Dixie Down," also a hit for Joan Baez, were popular on FM radio stations of the time.
Helm stayed with The Band through its 1976 farewell concert, which Martin Scorsese documented in his film "The Last Waltz." While the movie is regarded as perhaps the best rock 'n' roll documentary, Helm derided it and particularly Robertson, who he bitterly accused of preening for the camera, unfairly claiming writing credits and trying to appear the leader of the group in which all had been equals.
The estranged band mates appeared to make peace just days before Helm's death, when Robertson visited Helm in a New York hospital and later described him as "like an older brother" on Facebook.
Following some solo albums, Helm reunited in 1983 with The Band, minus Robertson. Manuel committed suicide while they were on tour in 1986. The remaining members - Helm, Danko and Hudson - released the final Band album in 1998.
Helm was diagnosed with throat cancer that year.
He earned a spot on Rolling Stone magazine's list of 100 greatest singers of all time. Jim James of the band My Morning Jacket wrote that "there is something about Levon Helm's voice that is contained in all of our voices. It is ageless, timeless and has no race. He can sing with such depth and emotion but he can also convey a good-old fun-time growl."
In 2007, Helm released his first solo studio album in 25 years, "Dirt Farmer," which picked up a Grammy award for best traditional folk album. In 2009, he released "Electric Dirt," winning another Grammy in the new Americana category. In 2011, he won for "Ramble At The Ryman" for best Americana album.
Helm also had a successful side career as an actor, using his aura of earthy dignity in movies such as "Coal Miner's Daughter," "The Right Stuff" and "The Three Burials of Melquiades Estrada."