Paul was born in Venice, a nephew of Pope Eugenius IV (1431–1447) through his mother. Through his father he was a member of the noble Barbo family. His adoption of the spiritual career, after having been trained as a merchant, was prompted by his uncle's election as pope. His consequent promotion was rapid; and the ambitious young cleric became a cardinal in 1440 and gained popularity through his generosity. He boasted that if elected pope he would buy each cardinal a villa to escape the summer heat.
After having been lay abbot of Santa Maria in Sylvis since 1441, in 1445 he succeeded Giuliano Cesarini as archpriest of the Vatican Basilica. Platina reported that Pius II suggested he should have been called Maria Pietissima (Our Lady of Pity), as "when he could not obtain what he aimed at by praying, entreating, and requesting, he would join tears to his petitions to make them the sooner believed." Some historians have suggested the nickname may also have been an allusion either to Paul's propensity to enjoy dressing up in sumptuous ecclesiastical finery, or possibly a lack of masculinity.