He was 88 and suffered from Alzheimer's.
Santos spent his entire career with Botafogo, who announced his death in a statement on Wednesday, and was a colleague of Pele at international level.
He is also credited with being one of the first to spot the genius of Garrincha after the mercurial winger took him on and beat him during a trial match at the Rio club.
Born in Rio in 1925, Santos signed for Botafogo as a teenager and never left. He represented the Rio side on 723 occasions and won six major titles, never losing a final.
He also played 84 times for Brazil and was in the squad not just for 1958 and 1962 but also in 1950 and 1954.
Santos was known for his runs down the wing, and many Brazilians credit him and his contemporary Djalma Santos with helping create the overlap. He is also known in Brazil as the Encyclopedia of Football due to his knowledge of the game.
His death means three players from the triumphant 1958 and 1962 sides have died this year. Djalma Santos passed away in July and goalkeeper Gylmar died in August.