On August 28, 1539, he became a canon of the cathedral chapter of St. Peter's Basilica. He became a Referendary of the Apostolic Signatura on June 1, 1549. He later served as an auditor at the Apostolic Palace.
He participated in the papal conclave of 1559 that elected Pope Pius IV. He opted for the titular church of Santa Croce in Gerusalemme on July 6, 1562, and then for San Clemente on November 7, 1565. He was a participant of the papal conclave of 1565-66 that elected Pope Pius V. Cardinal Capizucchi served as Camerlengo of the Sacred College of Cardinals from January 13, 1567 to January 14, 1568. On December 1, 1568, he became Prefect of the Apostolic Signatura. He also served as a member of the Holy Office.