In the Italian Wars Alfonso preserved his precarious position among the contending powers by flexibility and vigilance and the unrivalled fortifications of Ferrara; he entered the League of Cambrai against Venice and remained an ally of Louis XII of France even after Pope Julius II had made peace with Venice; when the Bolognesi rebelled against Julius and toppled Michelangelo's bronze statue of the Pope from above the gate, Alfonso received the shards and recast them as a cannon named La Giulia, which he set on the ramparts of the castello: in 1510 Julius excommunicated him and declared his fiefs forfeit, thereby adding Ferrara to the Papal States; Alfonso then fought successfully against the Venetian and Papal armies, winning the Battle of Polesella, capturing Bologna, and playing a major part in the French victory at the Battle of Ravenna (1512).

In the same ceremony, Ludovico married Alfonso's younger sister, Beatrice d'Este, the double wedding orchestrated by Leonardo da Vinci.

Their children were: After Lucrezia's death on 24 June 1519, he married Laura Dianti by whom he had had two illegitimate sons (later legitimized), Alfonso and Alfonsino d'Este.

There are documents from Mario Equicola on 9 October 1511, noting plans for painting of a room in Ferrara, in which six fables (fabule) or histories (istorie) shall be placed.

Dosso Dossi produced another large bacchanal, and he also contributed ceiling decorations and a painted frieze for the cornice, depicting scenes from the Aeneid, which gained immediacy by showing the heroes in contemporary dress (illustration, left).

Following in the lead of his father Ercole, who had made Ferrara into one of the musical centres of Europe, Alfonso brought some of the most famous musicians of the time to his court to work as composers, instrumentalists and singers.

Musicians from northern Europe who worked at Ferrara during his reign included Antoine Brumel and Adrian Willaert, the latter of whom was to become the founder of the Venetian School, something which could not have happened without Alfonso's patronage.