He studied law in Milan. In 1494, he became a member of the Collegio degli Avvocat in Milan. He became a consistorial advocate in 1505. He became an auditor of the Roman Rota in 1511 and served as the dean of the Roman Rota from 1522 to 1528. He also participated in the Fifth Council of the Lateran from 1512 to 1517.
On July 17, 1528, he was elected bishop of Pesaro. He was consecrated as a bishop on September 14, 1529 in the chapel of San Lorenzo in Piscibus by Cardinal Agostino Spinola. While Paolo Capizzuchi was absent from Rome, Pope Clement VII name Bishop Simoneta to replace him in the matter of the divorce of Henry VIII of England.
On December 20, 1535, he was named bishop of Perugia. He and six other cardinals were named on April 8, 1536 to a congregation for celebrating an ecumenical council. He was named bishop of Lodi on August 4, 1536, though he later resigned the government of the diocese in favor of his nephew Giovanni Simoneta on June 20, 1537. He opted for the titular church of Sant'Apollinare alle Terme Neroniane-Alessandrine on November 28, 1537. On December 10, 1537, he resigned the administration of Pesaro in favor of his nephew Ludovico Simoneta, who later became a cardinal himself.
A short time later, he became prefect of the Apostolic Signatura. On January 7, 1538, he and eight other cardinals were named to a second congregation charged with preparing for an ecumenical council. On February 6, 1538, he was appointed to the diocese of Nepi-Sutri. He resigned the government of Perugia on July 20, 1538.
He mediated a dispute between the Republic of Florence and the Republic of Siena for control over Montepulciano and was able to broker a mutually agreeable solution. In 1539, he was the papal legate to the Council of Vincenza, along with Cardinals Girolamo Alexander de Motta and Bonifacio Ferrero. On January 10, 1539, he became Camerlengo of the Sacred College of Cardinals.