On the death of Pope Innocent VIII in 1492, the 60-year-old Borgia wants the papal tiara at all costs (literally). He succeeds in buying the largest number of votes; Sforza, the Milanese candidate, being bribed with four mule-loads of silver. He takes the name Alexander VI and continues his love affair with Giulia Farnese, bringing his four adult bastard children under his protection and provision. Borgia must control rebels within the college of cardinals, as well as being faced with an invasion by Charles of France.
Alexander VI sends his son Giovanni (Juan) as head of his mostly Spanish army to subdue his enemies: the Orsinis. Juan proves an ineffective general and is brought home grievously wounded. Cardinal Cesare forbids the doctor's effective treatment as he wants to take Juan's place, but Juan recovers anyway. Lucrezia Borgia endures an unconsummated marriage until her father dissolves it. He exhibits an "excessive" love for her, resulting in a pregnancy. The pope sends the two sons (Cesare and Juan) to battle the family's enemies; Juan's drowned body is brought home, and Cesare finally feels he will be seen as his father's military strategist/leader.
Lucrezia, confined to a convent, confesses to Cesare (as a priest/cardinal) the identity of her unborn's father. A confrontation with the Pope results in Cesare's arranging the death of a scapegoat. Lucrezia's first husband is required to affirm his impotency to pave the way for her marriage to Alfonzo, with whom she falls in love. Cesare becomes part of an intrigue with Louis, the new king of France who has petitioned the Vatican for annulment of his marriage and a dispensation to marry his brother's widow. Cesare is released from holy orders and allowed to both marry and command an army to assist King Louis in his attempt to subdue Naples and Milan. Meanwhile, Lucrezia is pregnant again and her husband disappears in the night.
Lucrezia's husband returns from Naples to his pregnant wife, as ordered by the Holy Father. He regathers the family in Rome, and the child is born, christened Rodrigo. Cesare is appointed commander of the papal armies and summoned to quell a rebellion against the pope; he finds that Lucrezia's husband is conspiring against him. A plot to kill Pope Alexander is thwarted; Cesare defeats the cities of Imola and Forli and brings Caterina Sforza to Rome in triumph. An imprisoned nobleman, whose estates have been given to Lucrezia, is poisoned and her husband is attacked; Cesare is blamed. When Alfonzo is killed, Cesare threatens his father with exposure of honor-destroying secrets of the family, securing the pope's silence. Alexander counsels Lucrezia to cease grieving, but she vows never to forgive her father and brother.
Cesare Borgia has agreed to aid the King of France in regaining Naples in exchange for additional troops for his own army. Lucrezia continues to grieve, but the pope plots to use her to gain Ferrara--offering her hand to its prince. Cesare is sent to persuade her to return to Rome, where her father shares his plans. The war continues on the states resistant to the pope's control, and Cesare captures his mistress, recently a bride-by-proxy to a Venetian officer, taking her to Rome. Caterina Sforza is "ransomed" from the Castel Sant'Angelo by the French and surrenders title to her cities. Lucrezia's son Giovanni is legitimatized, and she is to marry the Duke of Ferrara-- "in name only," she promises Cesare.
Lucrezia is poised to marry the Duke of Ferrara, meeting with his representatives who seek to adjust the terms with the pope to their advantage. As meetings proceed, Cesare captures the man who writes calumnies of all the members of the Borgia family, torturing him to reveal his paymasters. The pope insists the cardinal accompanying Ferrara's men do the negotiation and intimidates him into favorable terms. Reluctantly, Lucrezia is required to leave her sons in Rome when she weds. Cesare returns to his plans to conquer the rebellious states: Florence, Naples, et al, with the help of machines designed by Leonardo da Vinci. During the summer retreat of the pope, Cesare has a political prisoner garroted. Niccolo Machiavelli observes him and later uses Cesare's exploits to illustrate what a Renaissance statesman should do, in his classic book, The Prince. Lucrezia is pregnant for the third time, and Jofre's wife Sancia is sent to the Castel Sant'Angelo after accusing the pope as a murderer.
Cesare again seeks Louis XII of France as an ally to gain an army since his condottieri have deserted him. He is even enlisting peasants and arming them. Lucrezia has had a still-born child and is being purged and bled by her doctors; Cesare suffers with her. The Orsini have joined the opposition and have enlisted a cardinal and a Spanish military leader; their intent is to defeat Cesare and depose his father. Negotiations between Cesare and the deserters seems to be making progress, but Alexander imprisons the blind cardinal sent to get his promise of no reprisals. The die is cast--there can be no compromise, one side must prevail, winner take all. Cesare succeeds in setting a better trap, captures and executes his enemies, and is both obeyed and feared throughout Romagna. Suddenly both Cesare and the pope are gripped by fever and excruciating stomach pains--is it poison?
Apparently making a good confession, Pope Alexander VI dies; Cesare is still weak from the unknown gastric attack; some rejoice, few mourn--a new pope must be selected. The cardinals are afraid to enter the Vatican because of Cesare's presence. They meet with him at the Castel Sant'Angelo, demanding the removal of all armed men of all factions from the city. Cesare's main objectives now are preserving his lands, his family and his treasure; he agrees to leave Rome. When a compromise is reached in the election of such an old man as pope that he could be considered an interim leader, Cesare returns and seeks Pius' protection. He offers to finance the coronation in exchange. He believes everything is falling into place, but Pope Pius dies! Cesare is left without a protector, surrounded by enemies.