Born in Rome, he was named cardinal by his uncle Urban VIII on August 30, 1627. Three years later he was made Legate in Urbino, and later in Avignon. He was also bishop of Poitiers, Frascati, Reims and Palestrina, as well as camerlengo of the Holy Roman Church. He was one of the leaders of the papal army in the war of Castro (1642-1644). After the ascenscion to the papal throne of Pope Innocent X he was accused of abuses and had to fly together with his brothers Francesco and Taddeo to France under the protection of Cardinal Mazarin. He reconciled with Pope in 1653 and returned to Rome. He became Vice-Dean of the Sacred College of Cardinals in March 1671; the dean at that time was his older brother Francesco Barberini (seniore).