He was born in Saint-Lô, in Normandy. His father was a physician, who on embracing the doctrines of the Reformation became a Protestant minister, and to escape persecution settled at Bern, in Switzerland. Here Jacques received his education, being taught Latin and mathematics by his father, and learning Greek and Hebrew and the philosophy then in vogue.
Returning to Normandy he was presented to the king by Jacques of Matignon; after he had abjured Protestantism, being again presented by Philippe Desportes, abbot of Tiron, as a young man without equal for knowledge and talent, he was appointed reader to the king. He was commanded to preach before the king at the convent of Vincennes, when the success of his sermon on the love of God, and of a funeral oration on the poet Ronsard, induced him to take orders. On the death of Mary, Queen of Scots, he was chosen to pronounce her eulogy. On the death of Henry III, after having supported for some time the cardinal de Bourbon, the head of the league against the king, Duperron became a faithful servant of Henry IV, and in 1591 was created by him bishop of Évreux.
He instructed Henry in the Catholic religion; and in 1594 was sent to Rome, where with Cardinal d'Ossat (15361604) he obtained Henry's absolution. On his return to his diocese, his zeal and eloquence were largely instrumental in withstanding the progress of Calvinism, and among others he converted Henry Sponde, who became bishop of Pamiers, and the Swiss general Sancy. At the conference at Fontainebleau in 1600 he argued with much eloquence and ingenuity against Du Plessis Mornay (15491623).
In 1604 he was sent to Rome as chargé d'affaires de France; when Clement VIII died, he largely contributed by his eloquence to the election of Leo XI to the papal throne, and, on the death of Leo twenty-four days after, to the election of Paul V. While still at Rome he was made a cardinal, and in 1606 became archbishop of Sens. After the death of Henry IV he took an active part in the states-general of 1614, when he vigorously upheld the ultramontane doctrines against the Third Estate.