On the death of his uncle Carlo (1485), he obtained the reins of his prominent house, at the time an enemy to the King of Naples and an ally of the pontiff.
Pope Sixtus IV appointed him general of his forces, which Virginio led to a victory over the Neapolitan army at the Battle of Campo Morto (1482).
It was with Neapolitan financial help that Virginio bought the Roman castles of Cerveteri and Anguillara from Franceschetto Cybo, the son of Pope Innocent VIII.
It seems that Alexander VI had already reached an agreement with Cybo over the two fortresses and their unexpected purchase by his chief vassal with Neapolitan money (40,000 ducats) was considered by the Pope as an act of treason.
He died probably of poison in the Castel dell'Ovo, in Naples (8 January 1497), while Alexander VI was confiscating the Orsini strongholds in the Papal States in favor of the Borgia family.