Sfondrati studied Ancient Greek and Latin as a young man and then received a doctorate of law from the University of Pavia. In 1518, he became a professor of public law at the University of Padua. He would later work as a professor at the University of Pavia, the University of Bologna, the Sapienza University of Rome, and the University of Turin. He was a counselor of Charles III, Duke of Savoy and a member of the senate of Turin. In 1527 and 1528, he was Podestà of Pavia. He was later a counselor of Francesco II Sforza, joining the senate of Milan in 1530.
Charles V, Holy Roman Emperor then named Sfondrati to the Aulic Council. He was also Charles V's ambassador to the Duke of Savoy. On October 23, 1537, the emperor made him Graf of Riviera di Lecco. He also served as governor of Siena.
Following his wife's death on November 20, 1538, Sfondrati entered the clerical estate. He quickly became a protonotary apostolic participantium. He also became a Referendary of the Apostolic Signatura.
On October 12, 1543, he was elected Bishop of Sarno. Pope Paul III then despatched Bishop Sfondrati as nuncio to Ferdinand, King of the Romans and the other princes of the Holy Roman Empire to discuss peace with the Kingdom of France and to promote the forthcoming ecumenical council. Sfondrati was promoted to the metropolitan see of Amalfi on October 27, 1544. He then served as nuncio to the Diet of Speyer (1544) to congratulate the emperor on his peace agreement with Francis I of France.
Pope Paul III made him a cardinal priest in the consistory of December 19, 1544. He received the red hat and the titular church of Santi Nereo e Achilleo on March 2, 1545. He also made him a member of the Roman Inquisition.
On February 25, 1547, the pope made Cardinal Sfondrati papal legate to the emperor to discuss plans for dealing with the Kingdom of England following the death of Henry VIII of England. This legation lasted until June 1548.
On March 23, 1547, he was transferred to the see of Capaccio. He opted for the titular church of Sant'Anastasia on October 10, 1547. On November 9, 1549, he was transferred to the see of Cremona.