The Mafia sweep netted 54 alleged members from three of the five families that run the Mafia in New York - the Gambino, Genovese, and Bonanno families - while a further eight of those indicted remained at large.
Prosecutors in New York unveiled a 170-page indictment against 62 individuals detailing murder, racketeering, loan sharking, conspiracy, drugs and extortion charges for crimes going back as far as the 1970s.
Among those facing charges were top Gambino leaders including acting boss John D'Amico, also known as 'Jackie the Nose', acting underboss Domenico 'The Greaseball' Cefalu and consigliere Joseph 'Miserable' Corozzo
US Attorney Benton Campbell says the charges struck at the core of the Gambino family.
"Today we serve notice that anyone who aspires to a position in organised crime will meet the same fate," he said.
Prosecutors say every member of the Gambino crime family administration not already behind bars was charged in the indictment.
The Gambino family was at the centre of the so-called Pizza Connection trial in the 1980s, one of the largest criminal cases in US history.
New York Police Commissioner Ray Kelly says he expects the indictment to have significant ramifications.
"You never can say that organised crime's wiped out - they're very resilient, they come back, they're very tenacious - but this is a major blow," he said.
Those charged faced jail terms of up to 20 years on each count of their indictments if convicted.
'Still a threat'
The deputy director of the Federal Bureau of Investigation (FBI), John Pistole, says the Mafia remain a major threat despite the sweep
"Today's arrests will be a major setback for the Gambino crime family, but it is a fallacy to suggest that La Cosa Nostra is no longer a threat to public safety," he said.
"Organised crime in New York is not dead."
Meanwhile, Italian deputy police commissioner Francesco Gratteri confirmed that 20 people were arrested in the Sicilian capital Palermo.
He says another three people were served arrest warrants in jail where they were already serving time for unrelated crimes.