In 1533, he moved to Rome, becoming a consistorial advocate. He was married to Antonina Capodiferro, the sister of Cardinal Girolamo Recanati Capodiferro and had a son. After Antonia died, Mignanelli entered the church. In 1537, he was sent as ambassador to the Republic of Venice to encourage Venice to break its alliance with the Ottoman Empire and to go to war against the Ottomans. In October 1537, Pope Paul III sent him as ambassador to Charles V, Holy Roman Emperor to present him with the brief postponing the Council of Trent for a second time. In spring 1538, he traveled to Nice with the pope to negotiate the end of the Italian War of 1536–1538; shortly thereafter, they traveled to Geneva to meet the emperor. On September 3, 1538, he was appointed nuncio to Ferdinand, King of the Romans, holding this position until 1539. In 1540, he became an auditor of the Roman Rota. He was also a protonotary apostolic and the pope's domestic prelate.