Settimo Mineo, 80, a lifelong member of the Sicilian mob who was recently released from prison, was allegedly appointed godfather at a secret summit in May to replace the mafia hitman Toto Riina, who died in jail previous year.
The 46 others could face charges of belonging to the mafia, extortion and illegal possession of arms amongst others.
Police are yet to release a comprehensive list of those arrested in Palermo, but revealed that Settimo Mineo, the head of the crime syndicate, was apprehended in the raids. "Mineo had been elected "heir" of Toto Riina after his death".
The cupola held a secret meeting in Palermo in May, the first gathering of mob families for 25 years, at which it reportedly made a decision to formally anoint Mineo as the head of Cosa Nostra.
Authorities are hailing the arrests as a dismantling of the upper echelons of the Cosa Nostra, which is believed to have been rebuilt after the death of "boss of bosses" Salvatore "Toto" Riina.
Palermo prosecutor Francesco Lo Voi recalled that Mineo had already served a lengthy prison sentence for Mafia association and other crimes after he was swept up in the maxi-trials against the Sicilian Mafia in the 1980s and 90s. As the eldest of the local clan leaders, he enjoyed particular respect, he said.
"And that despite the convictions, despite the trials, important people can take over the most important roles once they're back in play".
However, it did not continue to grow in strength at the same rate as the Calabrian-based 'ndrangheta or the Naples-based Camorra organised crime groups. But Italian officials said it continued increasing its financial and business activities.
Interior Minister Matteo Salvini called the sweep in Palermo an "extraordinary operation".