Alongside Mario, Orazio personally provided aid in the defense against Vieri de' Pazzi's ambush of Ezio Auditore da Firenze and the young noble's mother and sister when Ezio was just a mile from Monteriggioni's walls. As well as this, he helped to outfit and train Ezio during the first few months of his stay in the town.
The condottiero later explained to Ezio on the young man's request as to why Mario felt shame and anger towards Ezio when the latter had rejected his Assassin heritage and persisted in his choice to take his family to Spain once his combat training was complete.
Orazio later fought – although reluctantly – under Ezio when Mario had given Ezio command of a group mercenaries that Orazio was a part of during the first assault against Vieri's forces in San Gimignano, which later led to the assassination of the young Templar; Orazio ultimately died in the battle elsewhere in the city just as Ezio managed to strike down Vieri.
After showing Vieri's body its final respects, Mario told Ezio of Orazio's death, to which Ezio reacted with genuine shock and surprise. Mario then notified Ezio that Orazio's last words were to mention how brave Ezio had been during all the fighting, and suggested that Ezio should "live up to such praise".
- In Assassin's Creed: Renaissance, it is implied that Ezio and Orazio had formed a kind of friendship over the course of Ezio's training, particularly noted in Orazio's grim amusement of being placed under Ezio's command and Ezio's upset reaction when Mario informed him of his death.