He was diagnosed with cancer in July and "succumbed to underlying lung issues" surrounded by loved ones, a statement posted to his verified Instagram account said.
It did not mention when or where he died.
Just weeks after starting cancer treatment last summer, Weir had returned to his "hometown stage" at Golden Gate Park in San Francisco to play in a three-night celebration of his 60 years in music, his family recalled.
Those shows turned out to be his final live public performances, according to Rolling Stone magazine.
Along with his late fellow Grateful Dead co-founder and lead guitarist Jerry Garcia, who was at the centre of the universe for "Deadheads", as diehard Dead fans are known, Weir was one of the group's two frontmen and main vocalists for most of the band's history.
It was Weir who sang the verses on the band's trademark boogie anthem, Truckin', and who wrote such key songs as Sugar Magnolia, Playing in the Band and Jack Straw.
The youthful, ponytailed "Bobby" grew into an eclectic songwriter whose handsome appearance and diverse musical influences helped broaden the band's appeal.
British newspaper The Independent called Weir "arguably rock's greatest, if most eccentric, rhythm guitarist".
After Garcia's death at age 53 in 1995, Weir carved out an interesting if somewhat neglected solo career - much of it with his band, RatDog - and participated in reunions of surviving Dead members in different configurations.
Weir was the subject of the 2014 documentary The Other One: The Long, Strange Trip of Bob Weir, which made a case for the Dead's "other" guitarist as a musical force.
Weir, whose birth name was Robert Hall Parber, was born on October 16, 1947, and raised by adoptive parents in Atherton, California.
He did not excel in school, due in part to his undiagnosed dyslexia.
In 1964, at age 16, he met Bay Area folk musician Garcia, with whom he formed the Warlocks, which soon morphed into the Grateful Dead.
The athletic Weir, who enjoyed football, was the youngest member of the original band and was sometimes referred to as "the kid".
He was still in high school when he joined up with Garcia, bass guitarist Phil Lesh, organist-vocalist-harmonica player Ron "Pigpen" McKernan and drummer Bill Kreutzmann.
Weir's death leaves Kreutzmann as the only surviving original member. Founding bassist Lesh died in 2024.
In 2017, Weir was appointed as a United Nations Development Program goodwill ambassador to support the agency's work to end poverty while fighting climate change.
Weir married Natascha Muenter in 1999. They had two daughters.
"Looking back," Weir once said, "I guess I have lived an unusual life".
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