In the season one premiere, Rodrigo successfully bribes and intimidates his way into an election as Pope Alexander VI, making him the new leader of the Catholic Church.

The new Pope elevates his children to high office, installing Juan as head of the papal armies, Cesare as a cardinal and Lucrezia as a potential wife for a political ally.

Rodrigo seeks funds through a profitable marriage for Lucrezia that will ally him with Milan. Micheletto is ordered to rid his patrons of the ongoing threat posed by Della Rovere.

Lucrezia's financially and politically motivated wedding to Milanese nobleman Giovanni Sforza is a disaster thanks to Juan's inappropriately bawdy play in his sister's honor, Cesare's brazen flirting with a married baroness, and the arrival of the Borgia children's illegitimate mother.

The abused Lucrezia has an affair with a handsome stable boy; Cesare strikes a bargain with Machiavelli to thwart Della Rovere's invasion scheme, and ensures the baroness Ursual becomes a widow.

Della Rovere reaches France and strikes a bargain with its ruler to invade Italy and install him on the Papal throne in exchange for control of Naples. Rodrigo attempts to thwart the invasion through an alliance.

The invasion by King Charles of France and Della Rovere proceeds with victory seemingly inevitable as the French sack the city of Lucca and the Italian powers flee to their banner.

The invaders capture a fleeing and pregnant Lucrezia as they march on Rome, but she charms King Charles and is allowed to persuade her brother Juan to withdraw his hopelessly outmatched defensive troops.

Abandoned by even his cardinals, Alexander meets King Charles with humility and saves his throne. Della Rovere despairs as Charles abandons him. Lucrezia safely gives birth to a son in a convent as the Borgias secure an annulment of her marriage and plot revenge on their enemies.