Rodrigo successfully bribes and intimidates his way into an election as Pope Alexander VI, making him the new leader of the Catholic Church; powerful Cardinals Della Rovere and Orsini oppose his rise; the Borgias recruit a talented assassin named Micheletto to their cause.
The new Pope wastes no time consolidating power and balancing opposition to him in the College of Cardinals by elevating his children to high office, installing Juan as head of the papal armies and Cesare as a cardinal and his successor, while seeking a politically fortuitous marriage for daughter Lucrezia.
His coffers depleted by his expensive rise to power, Rodrigo seeks funds through a profitable marriage for Lucrezia that will ally with him Milan, and charges a fee for safe haven in the Holy City to Jews displaced by the Spanish Inquisition; the Borgias host a charming Turkish prince; 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; Della Rovere seeks the aid of the illustrious Medici family and their counselor, Machiavelli.
Alternately neglected and abused by her cruel husband, Lucrezia has an affair with Paolo, a handsome stable boy; Cesare strikes a bargain with Machiavelli: deny French troops passage across his masters' lands in exchange for suppression of Savonarola, a fiery preacher of anti-Medici sermons; in love with baroness Ursula, Cesare takes drastic action to get rid of her husband.
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 by marrying his youngest son Joffre to Princess Sancia of Naples (guest star Emmannuelle Chriqui), but Juan nearly sabotages the plan by seducing his prospective sister-in-law.
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, with Lucrezia's husband Giovanni Sforza poised to join them in the name of Milan; inventor Leonardo Da Vinci (guest star John Lynch) shows his drawings and blueprints for war machinery to the invaders.
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; Pope Alexander VI awaits to learn of his fate as Charles enters the city and makes his way to the Vatican.
Abandoned by even his cardinals, Alexander meets King Charles with humility and saves his throne, even eliciting a confession from the conqueror he crowns as the new "King of France and Naples;" 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.
Pope Alexander VI takes a new lover and throws a grand, pagan fete for the citizens of Rome when a cache of ancient artifacts is discovered; the rivalry between brothers Cesare and Juan spills into the streets; Lucrezia tends to her newborn child; now a pastoral priest once again, Della Rovere narrowly escapes an assassination attempt
The stable boy who fathered Lucrezia's child travels to Rome to rendezvous with her but suffers an unfortunate fate at the hands of Juan; the Pope's lovers Giulia and Vittoria take him in disguise on a revelatory tour of Rome's indigent.
Alexander VI refuses to allow a Catholic burial for Paolo, despite his doubts about the stable boy’s suicide, causing Lucrezia to embark on a hunger strike that threatens the life of her infant son; the French army heads back to Rome, allied with Sforza; Della Rovere slips back into the city unnoticed to launch a plot against the Pope’s life.
Cesare recruits a band of mercenaries with the help of Micheletto to seek revenge on the retreating French troops for burning the nunnery where his beloved Ursula lived; the Pope forges more strategic alliances and enriches himself in the bargain; Lucrezia joins Giulia's quest to aid Rome's poor.
Cesare deals with the cunning Sforzas decisively; Alexander disguises himself and travels to Florence to hear the fiery preacher Savonarola, not realizing that Della Rovere is trying to recruit the rebellious holy man to his cause.
Alexander is convinced that a lightning strike on St. Peter's Basilica during mass was a sign of God's disapproval; Cesare tries to prove his worth as a military commander; the Pope pressures the reluctant Lucrezia to enter another political marriage.
Juan's triumphant return from Spain is marred by his unsuccessful siege of the Sforza castle; Lucrezia purposely scuttles a scheme to marry her off to a rich Genovese merchant; Savonarola's forces conduct the infamous "Bonfire of the Vanities."
Juan returns to Rome trying to spin his combat injury as proof of his valor, but Cesare exposes his brother's ignoble behavior; Lucrezia takes a lover in her intended husband's younger brother; Della Rovere has recruited an angel-faced young friar as his suicide assassin, and the young man advances their agenda with a bold move against the Pope's food taster.
It's Easter and Alexander makes plans for a celebration to end his pious fast even as Della Rovere's assassin ascends to the position of the Pope's taster; Lucrezia's lover asks for her hand in marriage but her father dismisses him and his request; Juan's wild behavior threatens the life of Lucrezia's child, forcing Cesare to make a chilling decision about his brother.
Tragic news for the Borgia family is followed by a shocking revelation from Cesare; Lucrezia surprises herself by falling for a new suitor, Alfonso of Aragon, and accepts his proposal of marriage; Cesare tortures the rebel leader Savonarola but can't extract a confession, so he fakes one and burns the heretic; the assassin finally strikes with a poisoned chalice of wine.
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.
Devastated by his betrayal, Micheletto kills his lover and disappears. Cesare races to Naples to rescue Lucrezia. Brother and sister are eventually reunited and are so overjoyed to see one another that Alfonso begins to suspect that their relationship seems more than that of ordinary siblings. Alexander schemes to corner the market in Italian sulfur - the key ingredient to gunpowder.
Alexander and Cesare are reconciled at last. The Papal Armies have been fortified with the money saved from the Crusade and the proceeds of the Jubilee. Cesare marches his fearsome army to finish what Juan started - lay siege to Forli. Micheletto reappears. Following a scuffle with Cesare, a drunken Alfonso is near death and Lucrezia turns to her potions to end his life painlessly. Cesare vows that Lucrezia will now be his for good.
