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.

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.