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.

Alexander tasks Cardinal Sforza with purging the College of Cardinals, old Roman families conspire against the Pope, and Lucrezia tries to seduce Cesare.

The King of Naples refuses to accept Lucrzia's child as part of the marriage agreement and pointedly invites Caterins Sforza and other Borgia enemies to the wedding.

Cardinal Farnese exposes the embezzlement of Cardinal Versucci while the King of Naples insists the consummation of Lucrezia's marriage to his cousin be witnessed.

Lucrezia and Micheletto plot the death of King Ferdinand when he refuses her her baby as Cesare's promise of an annulment for Louis X!. gain him a wife and army.

Cesare unites the sons of the five Romagna families with his own army against Forli, and the Pope negotiates for a with Constantinople Jews for a holy relic.

After the French king occupies a deserted Milan, he tasks Cesare with killing Ludivico, and Lucretia becomes involved in Neapolitan palace intrigue.

Micheleto learns his kept lover is a Sforza informant, Caterina Sforza mounts the Shroud of Turin as a rival holy relic, and Alfonso puts Lucrezia under house arrest.

Lucrezia escapes with Alfonso and her baby from Naples while the Pope corners the market in sulfur, restricting others from manufacturing gunpowder.

Micheletto returns to Cesare briefly to help him destroy the walls of Forli and capture Caterina Sforza and later recruit her assassin Rufio.