Tommaso Parentucelli was born at Sarzana, Liguria, where his father, a physician, died while he Tommaso was young.

Parentucelli later became a tutor, in Florence, to the families of the Strozzi and Albizzi, where he had met the leading humanist scholars.

He had studied at Bologna and Florence, gaining a degree in theology in 1422.

Bishop Niccolò Albergati was so awestruck with Parentucelli’s capabilities that he had taken him into his service and given him the chance to pursue his studies further by sending him on a tour through Germany, France and England.

He has been able to collect books, for which he had an intellectual's passion, wherever he went.

Some of them survive with his marginal annotations.

He had attended the Council of Florence, and in 1444, when his patron died, he had been appointed Bishop of Bologna in his place.

Civic disorders at Bologna were prolonged, so Pope Eugene IV soon named him as one of the legates sent to Frankfurt, where he was to assist in negotiating an understanding between the Papal States and the Holy Roman Empire, regarding undercutting or at least containing the reforming decrees of the Council of Basel (1431–1439).

His successful diplomacy had gained him the reward, on his return to Rome, of the title Cardinal-Priest of Santa Susanna in December 1446.

At the papal conclave of 1447, he is elected Pope in succession to Eugene IV on March 6.

He takes the name Nicholas V in honor of his early benefactor, Niccolò Albergati.