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.

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.