The son of Girolamo Orsini and Francesca Sforza, he was grandson, on his father’s side, of Felice della Rovere (illegitimate daughter of Pope Julius II) and Gian Giordano Orsini and, on his mother’s side, of Count Bosio Sforza and Costanza Farnese, an illegitimate daughter of Pope Paul III. On 3 September 1558 he married Isabella de" Medici, daughter of Cosimo I de" Medici, Grand Duke of Tuscany, at Poggio a Caiano.
In 1571 he took part to the battle of Lepanto. A year later, in October 1572, he served as a general of the Spanish infantry, in a campaign that tried to reclaim the garrison of Navarino in the Peloponnese. One scholar, Elisabetta Mori, has argued that Isabella de" Medici died of natural causes and that the rumour that Paolo Giordano murdered her was spread by enemies of the Medici.
He died at Salò on 13 November 1585.
On 22 December Vittoria was herself assassinated, by Ludovico Orsini of the Monterotondo line, on the instigation of Grand Duke Francesco.
He was a member of the Roman family of the Orsini.
