The Cosa Nostra leader died at 3:37 am on Friday in the hospital unit of the prison in the northern Italian city of Parma.
He was in a medically-induced coma following surgery at the time of his death.
There was no plan for a public funeral since Mr Riina was a convicted mafioso.
The violent mobster was serving 26 life sentences and is believed to have ordered more than 150 murders.
Nicknamed “The Beast” for his brutality, Mr Riina ordered the assassinations of anti-Mafia magistrates, Giovanni Falcone and Paolo Borsellino, 25 years ago.
He coordinated the assassination of Carabinieri General Carlo Alberto Dalla Chiesa, who had just been appointed prefect of Palermo, in 1982.
He also orchestrated the kidnapping, strangling and dissolving in acid of the young son of a mob informer.
Despite dying behind bars, Mr Riina was reportedly considered the head of Cosa Nostra until his death.
In July, a Bologna court rejected a request from Mr Riina’s lawyers for him to be released to house arrest due to his deteriorating health.
Italian Foreign Minister Angelino Alfano said on Friday that he was not sorry to hear of the murderous criminal’s death.
“Totò Riina is dead, and as of today Italy is a better place,” Mr Alfano said in New York.
“My thoughts are with all [of Mr Riina's] victims and their families.”