Generally known as a skilled diplomat who played a major role in the election of Rodrigo Borgia as Pope Alexander VI, Sforza served as Vice-Chancellor of the Holy Roman Church from 1492 until 1505.

While still an adolescent, Ascanio was promised the red hat of a cardinal of the Roman Catholic Church by Guillaume d'Estouteville, who wanted to gain Galeazzo Maria Sforza's support for his candidacy for the papal throne in 1471.

However, it was in fact Francesco della Rovere (Sixtus IV) who won the papal election, and Ascanio's promotion to cardinal was delayed.

[4] Hoping to pacify Milan, Sixtus IV attempted to create Ascanio a cardinal in 1477 but the Sacred College refused to accept him into its ranks.

[citation needed] Nevertheless, Ascanio entered the episcopate[disputed – discuss] when he was appointed Bishop of Pavia in September 1479, retaining the diocese until his death.

Balue had suggested that Innocent VIII summon René II, Duke of Lorraine to retrieve his rights over the Neapolitan throne – leading to a violent quarrel with Ascanio; to which only the pope could bring a halt.

[citation needed] In 1490 Sforza commissioned Bramante and Giovanni Antonio Amadeo to construct the Chiostro Grande ("large cloister") and the chapterhouse at Chiaravalle.

[13] Ferdinand hoped to arrange a marriage between another of King Ferrante's grandsons, Don Luigi d'Aragona, with a member of Pope Innocent's family, Battistina Cibò.

[14] At the same time, Ferdinand of Capua was seeking to obtain the investiture of Naples from the Pope, thereby solidifying his family's hold on the Kingdom, to the prejudice of René II, Duke of Lorraine, the French claimant.

[citation needed] In the Conclave of August 1492, after having accepted that he would not be able to obtain the papal tiara for himself, Ascanio promised his vote to Rodrigo Borgia, then-Vice-Chancellor of the Holy Roman Church.

In addition he would receive the castle at Nepi, the Bishopric of Eger (which had an annual income of 10,000 ducats), two canonries, and the office of Prior of a convent in the diocese of Calahorra which was held by Borgia.

[18][19] In order to strengthen the relationship between his family and the papal house, Ascanio arranged the marriage of Giovanni Sforza, his cousin and governor of Pesaro, to Lucrezia Borgia, the Pope's illegitimate daughter, in 1493.

Ludovico Sforza having secretly allied himself with King Charles VIII of France, Ascanio betrayed the Pope together with several cardinals and clamoured for his deposition under della Rovere.

[citation needed] When the French again invaded Italy with the support of the Holy See, Ascanio watched his brother Ludovico Sforza's downfall and imprisonment (1500), unable to act.

He made futile efforts to succeed Alexander VI, fighting against Cardinal della Rovere and Georges d'Amboise, the formal nominee of France.

When Pius III (Francesco Piccolomini) died the same month of his coronation, Cardinal Sforza took part in the Papal conclave, October 1503, but Giuliano della Rovere (Julius II) was elected nearly unanimously.