The cause of death was attributed to complications from an operation to remove a brain swelling, the Italian news agency ANSA reported.
Manganelli, 63, led Italy's police force since June 2007.
Born in Avellino, Manganelli earned a law degree from Naples University and a post-graduate degree in criminology from Modena University.
He taught at Italy's top police academy and authored a number of publications on topics ranging from investigative techniques to kidnappings.
Manganelli was the No. 2 man in an elite 1980s crime-fighting unit that worked closely with anti-Mafia magistrates Giovanni Falcone and Paolo Borsellino.
Both men were killed by Cosa Nostra bombs in 1992.