Riina, who had been serving 26 life sentences and is thought to have ordered more than 150 murders, had been in a medically-induced coma after his health deteriorated following two operations.
The mobster, who turned 87 on Thursday, died in the prisoners' wing of a hospital in Parma in northern Italy just before 4:00am, a ministry of justice spokesman told AFP.
Nicknamed "The Beast" because of his cruelty, Salvatore "Totò" Riina led a reign of terror for decades after taking control of the island's powerful organised crime group Cosa Nostra in the 1970s.
"Riina will go down in history as the man who destroyed Cosa Nostra," newspaper La Repubblica's mafia expert Attilio Bolzoni said.
"With his strategy of bloody massacres in Sicily and across Italy... he turned an invisible mafia visible, with hundreds, thousands of murders, carried out first with Kalashnikovs, then bombs".
The most high-profile murders he ordered were those in 1992 of anti-mafia judges Giovanni Falcone and Paolo Borsellino, who had worked fearlessly to bring more than 300 mobsters to trial in 1987.
The remains of a police car destroyed during of the assassination of judge Giovanni Falcone, now a memorial in Palermo. Photo: Marcello Paternostro/AFP
He also famously ordered the brutal murder of a 13-year-old boy who was kidnapped in a bid to stop his father from spilling mafia secrets. The boy was strangled and his body dissolved in acid.
"God have mercy on him, as we won't," an association for victims told the Fatto Quotidiano daily.
The Italian bishops conference ruled out a public church funeral for the mass murderer. Pope Francis declared all mafiosi "excommunicated" from the Catholic Church in 2015.
Riina, who was also dubbed "U Curtu" ("Shorty") due to his 5-foot-2-inch height, for years denied all links to the crime group.
In 2009 he broke the mafia code of omerta – a vow of silence –and surprised those who thought he would take his secrets to the grave by admitting his link to the mob.
He was caught on a wiretap earlier this year saying he "regrets nothing".
"They'll never break me, even if they give me 3,000 years" in jail.
Toto Riina after his arrest in 1993. Photo: Italian police handout/AFP
The son of a poor farmer, Riina was born on November 16, 1930 in Corleone, a village inland from Palermo and the birthplace of Don Corleone, the fictional Godfather in Francis Ford Coppola's popular movie trilogy.
He is believed to have first murdered for the Mafia aged 19 and followed that a year later by killing a man during an argument – landing him behind bars for a six-year manslaughter stretch.
Once out, he became a foot soldier for volatile boss Luciano Leggio, eventually taking over from him at the end of the 1970s when the cigar-puffing fugitive was caught and jailed.
Riina went on the run himself in 1969, but continued to lead the Corleonesi clan from hiding, increasing his influence by bumping off rivals such as Filippo Marchese, a hitman who garroted his victims in a "room of death".
Riina would elude police efforts to snare him for almost a quarter of a century – without ever leaving Sicily – and took charge of Cosa Nostra's key businesses, from drug trafficking to kidnapping and racketeering.
His bloody victory in the Mafia War of the 1980s was to prove his undoing, however, as mobsters from defeated rival families began turning state witness against him, and police tracked him to a house in Palermo.
The village of Corleone, Sicily. Riina's land there was confiscated and turned into a B&B. Photo: Filippo Monteforte/AFP
In revenge for Riina's arrest and a new anti-mafia law that saw jailed mobsters kept in total isolation, the group launched a series of bombings in Rome, Milan and Florence that killed 10 people.
After years in which only his lawyers were allowed to visit him, an ageing and cancer-riddled Riina asked in July 2017 to be released from prison on the grounds of serious illness – a request that was denied.
On Thursday, days after he was placed into a medical coma by prison doctors, Italy's Health Minister Andrea Orlando signed a waiver allowing Riina's family to visit him and say their goodbyes.
The mobster was married to Antonietta Bagarella, a teacher from a mafioso family. He was father to four children, one of whom is behind bars for four murders.
"You're not Toto Riina to me, you're just my dad. And I wish you happy birthday dad on this sad but important day, I love you," one son, Salvo, wrote on Facebook on Thursday.
The mobster's eldest daughter Maria Concetta mourned by posting a picture on Facebook of a finger pressed to the lips and the word "shhh...", a likely reference to the mafia code of silence.