Denaro, who is allegedly the boss of the notorious Cosa Nostra mafia, was reportedly detained from a private clinic in Sicily's capital Palermo.
Italian PM Giorgia Meloni praised the arrest of the mafia as a "great victory for the State".
"My warmest thanks and those of the entire government go to the police forces, in particular to the Carabinieri Ros section, the National Anti-Mafia Prosecutor's Office, and the Palermo Prosecutor's Office, for the capture of the most significant figure in the mafia," she was quoted as saying by ANSA.
More than 100 members of the armed forces were reportedly involved in the arrest.
Messina Denaro was tried and sentenced to life in jail in absentia in 2002 over numerous murders, reports BBC.