[3] On becoming a clergyman, he was elected Bishop-Coadjutor of Pistoia in 1509, assuming the diocese in September 1518[4] but resigning it that November in favour of his nephew Antonio Pucci.

Pope Leo X made him a cardinal in the 23 September 1513 consistory (with the titulus of Santi Quattro Coronati) and chose him as his personal secretary, in which role he was sent on several ambassadorial missions, especially to Florence, where the pope wanted gonfaloniere-for-life Piero Soderini to retire from office.

He was a patron of the arts, notably of Michelangelo and Raphael, whilst in 1520 he also became the dedicatee of Erasmus' edition of the Works of St. Cyprian.

Under pope Adrian VI, Pucci was accused of fraud in connection with the sale of indulgences, but he escaped punishment thanks to the intercession of Cardinal Giulio Medici, who after his election to the papacy in 1523 as Pope Clement VII cleared Pucci of all charges.

Upon the post-war rapprochement which Clement and Charles soon reached, Pucci was one of the keenest advocates of quickly reconquering Florence from Republican rebels.