FOLLOWING THE TREATY of Bagnolo in 1484, Eleonora d’Aragona turned her attention to her children's futures. Her two daughters, Isabella and Beatrice d’Este, were already betrothed to Francesco Gonzaga, future marquis of Mantua, and Ludovico Sforza, the de facto ruler of Milan, respectively. The heir-apparent, Alfonso d’Este, was engaged to Anna Sforza, solidifying the growing closeness between Ferrara and Milan. This left three other children, Ferrante, Ippolito, and Sigismondo. Ferrante d’Este was still in Naples, where he would remain until 1489. Sigismondo, the youngest of Eleonora and Ercole's children, grew up in Ferrara and spent much of his life as his elder brother Alfonso's companion. Ippolito, however, was given special attention. At the age of three, he received in commendam the abbey benefice of Casalnovo. Three years later, he became the commendatory abbot of the Benedictine monastery, S. Maria di Pomposa, in the diocese of Ferrara, launching his ecclesiastical career.

Meanwhile, Ippolito's grandfather had become embroiled in yet another war. On September 26, 1485, rebel barons captured the hillside city of Aquila in the Aterno river valley. This was followed by the fall of Salerno and the seizure of Federico d’Aragona, Ferrante I's youngest legitimate son. In October, Pope Innocent VIII declared war against the king of Naples in response to unpaid annual tributes. Innocent also invited Jean II, duke of Lorraine, to join the fray because the duke had a claim to Naples through his Angevin ancestors but the duke never arrived. Venice, however, allowed the famed condottiero of the War of Ferrara, Roberto Sanseverino, to fight on behalf of the pope. In the interim, Ferrante I gathered reinforcements and, with the support of Florence and Milan, recaptured Aquila. The rebels met with Ferrante in Miglionico, where the king agreed to pay the annual papal tribute with arrears, grant amnesty to the rebels, and permit the people of Aquila to determine their ruler. However, Ferrante reneged on the treaty and arrested several of the ringleaders during the wedding of Maria Piccolomini and Marco Coppola at the Castel Nuovo in Naples. In the following weeks, he forced the removal of papal troops from Aquila, ordered the papal ambassador's assassination, and sequestered the rebels’properties.