Francesco resided for a time at the papal court, keeping his uncle Cardinal Ercole, who retired to his native Mantua, informed on the affairs of the Curia, the intrigues and factional struggles that took place there, and on the relations of Pius IV with his Borromeo relatives and with the princes. Cardinal Ercole was an influential participant in the Council of Trent. Francesco's letters, almost always inspired by Cardinal Borromeo and revised and corrected by him, constituted an indirect means often used by the pope to communicate his decisions to Ercole Gonzaga. In turn, the cardinal supplied his nephew, first from Mantua, then from Trento - where he had gone on 16 April 1561 to preside over the college of legates of the council -, suggestions, and advice and information.[1]
On 2 March 1562 he was elected Archbishop of Cosenza with dispensation for not having reached the canonical age; he was named administrator of the see.[2] He never set foot there, preferring to govern it through a vicar. He was a member of Borromeo's literary Academy of the Vatican Knights which met at the Casina Pio IV. His brother Cesare was also a member.
On 16 July 1562 he opted for San Lorenzo in Lucina, a titular church declared to be a deaconry pro illa vice. He opted for the order of cardinal priests on 1 March 1564 and San Lorenzo in Lucina was returned to its status as a titular church at that time. He resigned the government of the Archdiocese of Cosenza sometime before 12 January 1565. On 5 May 1565 he succeeded his cousin Federico Gonzaga (cardinal) as Bishop of Mantua with dispensation for not having reached the canonical age.[2]
He arrived ill at the papal conclave of 1565-66 that elected Pope Pius V and died during the conclave, in Rome, on 6 January 1566 at the age of twenty-eight.[3] He was buried in the choir of San Lorenzo in Lucina. The following month his brother Cesare, count of Guastalla, held an ornate commemoration in the Cattedrale di San Pietro apostolo in Mantua, including a large catafalque with an Egyptian motif.[3]