Lucrezia is inconsolable after Paolo's death, but it is ruled a suicide as King Charles marches north to revenge themselves on the Pope and the Eternal City.
The Pope excommunicates Friar Savanarola and he fails a test by fire while Giovanni haunted by shame and the agonies of syphilis threatens Lucrezia's son.
Thanks to Lucezia's remedy for cantarella, Rodrigo makes a miraculous recovery to everyone's surprise, but there is a Sforza plot to kill the Pope's family.
The Pope disarms King Charles by promising his support for his Neapolitan claims, and wishes to annul Lucrezia's marriage on grounds of her husband's impotency.
Paolo helps Lucrezia and Guilia escape Sforza, but they are captured by advancing French forces as the Pope's cardinals flee Rome before King Charles' military juggernaut.
Cesare learns that Ursula and others at the convent have been slaughtered by the French, and he plans revenge as the Pope organizes a coalition to attack the retreating French.