Riario was the nephew of Pope Sixtus IV, and secured his power early in life using his connections to the church. In 1473, he was married to Caterina Sforza, daughter of Galeazzo Maria Sforza, the Duke of Milan. The couple resided in Rome during Sixtus' pontificate, where Riario gained a reputation for being one of the most ruthless nobles at court. After the death of the Pope's brother, Riario secured the titles of Lord of Imola and Forlì.
Riario became a prominent enemy of Lorenzo de' Medici, leader of Florence, and the latter contracted his Assassin ally Ezio Auditore da Firenze to thwart several of Riario's plans in Forlì and Romagna.
Until his death, Riario continued to aid the Borgia family in their attempts to conquer Italy, working on a map that detailed the locations of the pages of Altaïr Ibn-La'Ahad's Codex. In 1488, Caterina hired Checco and Ludovico Orsi to murder her husband. The Orsi brothers infiltrated Riario's home, stabbed him to death, and looted his residence. Riario's naked corpse was then thrown in the center of the town square.
His son, Ottaviano, succeeded him as Lord of Imola and Forlì, with Caterina Sforza serving as regent.
- Historically, Girolamo Riario was one of the leaders of the Pazzi conspiracy against Lorenzo de' Medici. During Assassin's Creed II, he is never identified as a member of the conspiracy, despite his enmity to Lorenzo sometimes being alluded to in assassination contracts.