The former full back, who won the World Cup in 1958 and 1962, passed away due to a lung infection.
The former Selecao left back had been admitted to hospital in Rio de Janeiro with respiratory issues on Saturday, having suffered with Alzheimer's disease for half a decade.
Santos spent the entirety of his 16-year playing career at Brazilian side Botafogo, making 729 appearances for the club alongside 75 caps for the national side, pioneering the overlapping full back technique which is so common is modern football.
Brazil's football federation (CBF) president Jose Maria Marin sent his condolences to Santos' bereaving relatives soon after news of his passing broke on Wednesday.
"I had the privilege of seeing the play Nilton Santos," he told the CBF website. "He was one of the greatest in the world, at all times, even being a wide defender.
"He played football with an elegance and technique, he had talent to spare. Brazilian football is in mourning and has decreed the observance of a minute's silence in all matches from competitions organized by the entity."
Nilton Santos, who played at four World Cups, is the third player from the 1958 and 1962-winning Brazil players to have died in 2013, following Djalma Santos and Gylmar.