Early in his career, he joined the Knights Hospitaller. Pope Leo X made him a cardinal while he was still a layman. However the promotion was contingent on certain conditions that Sanseverino never complied with, so his elevation to the cardinalate was never published and neither Pope Leo X nor Pope Adrian VI ever recognized him as a cardinal.
Pope Clement VII made him a cardinal priest in the consistory of November 21, 1527. He received the red hat and the titular church of Santa Susanna from Cardinal Lorenzo Campeggio in the Castel Sant'Angelo on April 27, 1528. He received the tonsure from Cardinal Alessandro Farnese.
On August 31, 1528, he was elected Archbishop of Taranto. He occupied that see until his death. He was the administrator of the see of Conversano from July 28, 1529 to February 11, 1534. He was the Camerlengo of the Sacred College of Cardinals from January 24, 1530 to January 18, 1531. He opted for the titular church of Sant'Apollinare alle Terme Neroniane-Alessandrine on May 16, 1530. He was consecrated as a bishop by Pope Clement VII in the Sistine Chapel on December 21, 1531. On September 5, 1534, he opted for the titular church of Santa Maria in Trastevere.
On November 28, 1537, he opted for the order of cardinal bishops and received the suburbicarian see of Palestrina. He was the papal legate (along with Cardinals Lorenzo Campeggio, Giacomo Simoneta, and Giralomo Aleandro) to the general council held at Mantua then at Vicenza.