The son of a physician, he received an excellent education, made the acquaintance of distinguished scholars in Rome, and became a close friend of Cardinal Marcello Cervino, later Pope Marcellus II.

He prepared for Cervino, who was President of the Council of Trent in its initial period, extensive reports on all the important questions presented for discussion.

After his appointment as custodian of the Vatican Library, Sirleto drew up a complete descriptive catalogue of its Greek manuscripts and prepared a new edition of the Vulgate.

There was talk of making him Pope, but it was considered that the drift of his mind was too much given to letters to permit him to run a strong, practical administration in those troubled times.

Highly appreciative of Greek culture, he entertained all friendly relations with the East and encouraged all efforts tending to ecclesiastical reunion.