Pope Alexander fights for his life; the cardinals fight for control of the papacy; Cesare and Micheletto track the assassin; Della Rovere prepares to make his move.
Pope Alexander tasks Cardinal Sforza with initiating an inquisition among the Cardinals who were politicking against him. With the evidence he needs, Alexander dismisses and banishes all the Cardinals he does not trust. Meanwhile, Catherina Sforza orders Rufio to seek support from the mercenary warlords of the Romagna families. Lucrezia is annoyed with her in-laws to be and her situation is complicated further as she realizes her feelings for Cesare are becoming something more than sisterly.
As the purged Cardinals are dismissed and stripped of their titles and wealth, one of them angrily sets the Vatican treasury ablaze. Incensed by the new King Ferdinand's arrogant refusal to accept Giovanni as Lucrezia's child, Cesare travels to Naples to fix the problem. After Lucrezia and Alfonso's wedding, Alfonso realizes that the political sands are shifting - and not in his favor. Upset, he abandons Lucrezia alone on their wedding night, driving her into the arms of someone else.
Newly appointed Cardinal Farnese is placed in the Treasury and quickly discovers Versucci's theft. Micheletto is sent to find the wayward Cardinal. Meanwhile, upon hearing of Venice's request for help, Alexander, seeing this as an opportunity to replenish the coffers, dramatically calls for a Crusade. The Cardinals participate in the "banquet of chestnuts". Elsewhere, King Ferdinand learns that Lucrezia and Alfonso's marriage has not been consummated.
Cesare's diplomatic mission to France is a success, with the help of his old advisor Machiavelli. Back in Rome, the seductive and dangerously insane Bianca makes a drastic statement. Lucrezia travels to Naples accompanied by her husband and Micheletto. King Ferdinand remains steadfast in his determination that little Giovanni will not be recognized at court. Upon learning this, Lucrezia plots against him.
When Cesare lands in northern Italy with a French army, Alexander is furious at what he sees as a challenge to his authority, but reluctantly accedes to Cesare's plan to destroy the Sforza dynasty. Catherina, meanwhile, has come up with a plot of her own: biological warfare. Concerned about the lack of funds for his Crusade, Alexander imposes punitive taxes on the newly arrived Jewish community.
Cesare burns Constanzo's palace in order to contain the plague. Lucrezia, aware that the political wind has changed towards France, seeks a Neapolitan power base for herself and her family. Lucrezia blackmails Prince Raphael and Prince Frederigo replaces Ferdinand as King.
Pilgrims are flooding to Rome for the Jubilee year celebration, but Catherina Sforza has a plan to ruin Alexander's lucrative festival. Meanwhile, Lucrezia senses a change in newly crowned Frederigo and realizes that she is under constant watch from the royal guard. A plot to deceive the Borgia family is uncovered by Lucrezia, Cesare and Micheletto.
Cesare and Lucrezia are reunited but Alfonso begins to suspect them.
Season 3 finale. Cesare vows that Lucrezia will now be his for good.