Mayall, who lived in the Los Angeles area for much of his life after leaving England in the 1960s, died peacefully at home on Monday, his official Facebook page announced.
He was 90 and survived by six children, seven grandchildren and four great-grandchildren.
"Health issues that forced John to end his epic touring career have finally led to peace for one of this world's greatest road warriors," the page stated. "John Mayall gave us ninety years of tireless efforts to educate, inspire and entertain."
The godfather of British blues, Mayall was known in rock history as much for his own music as for the musicians who went on to greater fame after spending time in his Bluesbreakers. Clapton may be the most famous of those, but Peter Green, John McVie and Mick Fleetwood went on to found Fleetwood Mac, Jack Bruce formed Cream with Clapton and Mick Taylor joined the Rolling Stones in the 1970s.
Mayall moved to the Laurel Canyon area of Los Angeles - a neighborhood known as home to many influential musicians of the period - in 1969.
He is being inducted into the Rock and Roll Hall of Fame this year.
He continued to perform well into his 80s. His last show was at the Coach House in San Juan Capistrano in 2022, Variety reported.