ON SEPTEMBER 2, 1494, Charles VIII crossed the Alps over the pass of Montgenèvre with a land army of 31,500 men and 10,400 more to arrive by sea. By September 5 he was in Turin and, after being temporarily waylaid by smallpox, reached the city of Asti on October 6. He had a claim to the Neapolitan throne through his Angevin ancestry and swept through Italy with little mercy for those who dared resist. Alfonso II abdicated the throne before Charles’ arrival in favour of his son, Ferrandino, but not before divesting the treasury of its gold to fund his escape to a monastery.

By February 1495 the King of France had seized Naples with negligible Aragonese opposition. The French king's violent armies shocked the Italians who were not accustomed to the bloody nature of the Swiss mercenaries, having mostly fought among themselves. However, Milan and Venice decided to cauterize his seemingly inevitable conquest of Italy. On March 31, the Holy League was established which included the Republic of Venice, the Duke of Milan, the Pope, the Catholic Monarchs, the King of England, and the Holy Roman Emperor, Maximilian I.

Francesco II Gonzaga, Marquis of Mantua and Isabella d’Este's husband, was charged with gathering an army and expelling the French from Italy. While Gonzaga was amassing soldiers, Charles VIII was crowned king of Naples on May 12, 1495. The civic unrest of the Neapolitan people, however, forced its new king out of the city by early July. As Charles was retreating northward from Naples, Francesco Gonzaga's army met him in Fornovo di Taro, a town near Parma. The Battle of Fornovo was a watershed battle in the first decade of the Italian Wars. Although both sides claimed victory, and the Italians suffered heavy losses due to French artillery, Charles VIII eventually left Italy, abandoning his conquests in the north.

Ferrandino was returned to power in July 1495, with the Venetians’ assistance, in exchange for access to key ports in Naples. However, the French viceroy, Gilbert, Count of Montpensier, continued to resist. The Neapolitans were assisted by Spanish infantry, led by Gonsalvo de Córdoba, and the French were expelled from Naples by July 1496. In the same month, the twenty-seven-year-old Ferrandino married his seventeen-year-old aunt, Juana II, which required papal dispensation.