His military career spanned 40 years, serving French royals, Kings of Naples, Dukes of Milan, Popes, the Catholic Monarchs of Spain and Charles V, Holy Roman Emperor.

After some other battle deeds, Prospero, who had joined Cardinal Giuliano della Rovere's party, was imprisoned in Castel Sant'Angelo (Rome) by Pope Alexander VI.

While the Neapolitan king Frederick IV fled to the island of Ischia, Fabrizio and Prospero Colonna tried to defend the kingdom., but were defeated and imprisoned in the Castel Nuovo of Naples.

Eventually ransomed, both cousins then introduced themselves to the Spanish general Gonzalo Fernández de Córdoba, the "Great Captain", and entered the service of the Catholic Monarchs of Spain.

After Fernando de Andrade defeated the French in Seminara, the Great Captain abandoned Barletta and crossed the Ofanto, establishing a in Cerignola which Colonna helped fortifying.

[5] Colonna pursued the remnants of the French to their camp with part of their heavy cavalry, and he and his entourage allowed themselves to sleep in d'Armagnac's tent, causing worry among the Spanish when they didn't return until next morning.

The Spanish had been reinforced by Bartolomeo d'Alviano, a condottiero from the Orsini family and an old rival to Colonna, who assisted the Great Captain and Prospero at assaulting the French positions during the Battle of Garigliano.

He received offers from the Republic of Florence to lead their armies, but he stayed in the service of Spain, being entrusted with taking the captured Cesare Borgia to the peninsula.

After the death of Queen Isabella, Córdoba's main benefactor in the Spanish court, Colonna secretly slandered him to King Ferdinand, warning about the enormous Italian support to the viceroy and how easy it would be for him to revolt and take Naples for himself.

Around this time, he added Itri, Sperlonga, Ceccano, and Sonnino to his fiefs, and was also able to take back his territories in the Lazio after the Pope's death, becoming once again a great feudal lord in southern Italy.

After Venice suffered a crushing defeat in the Battle of Agnadello, Colonna assisted the new Viceroy of Naples, Ramón de Cardona, in taking the Venetian colonies of Monopoli, Mola, Polignano and Trani.

He eventually returned in autumn under much pressure by Pope Julius II and Cardinal Francisco de Remolins, rejoining the Spanish in the Po and being appointed captain general of Milan under Maximilian Sforza.

However, the French general Jacques de la Palice surprised him by going through the pass of Argentera, considered unpassable for any sizable army, but accessible to him by the help of Milanese condottiero Gian Giacomo Trivulzio.

In 1518, due to the arranged marriage between King Sigismund I of Poland and Isabella's daughter Bona Sforza, Colonna organized the ceremony in Naples, and later escorted the couple to Kraków.

[5] In 1521, he was chosen by Charles V and Pope Leo X as the commander of the combined Imperial-Spanish and Papal troops during the Four Years' War, leading the effort against France and Venice.

Colonna had to join forces with d'Ávalos and the Papal representative Federico II Gonzaga, Duke of Mantua, as well as Giovanni delle Bande Nere.