In 1529 he was appointed bishop of Rodez, and he was soon joined by his secretary and life companion, the humanist Guillaume Philandrier (1505–1565), the commentator on Vitruvius , who provided, under Armagnac's patronage, the design for the new cathedral façade at Rodez and catalogued the Bishop's increasing library.
He was sent as ambassador to Venice, 1536–39, where he took the opportunity to sit to Titian for a highly personal and evocative double portrait with the attentive Philandrier, whose commentary on Vituvius, the first in French, was completed in 1544. Armgnac's brief was to secure Venetian neutrality in the north Italian military conflicts between Francis I and Charles V, an episode of the Italian Wars. The emperor's failure to take Avignon led him to retreat from the south of France (1538). With the temporary truce of 1539 the king sent him as ambassador to the Holy See, where he was made a Cardinal in December 1544, remaining as ever the agent of French policy. He participated in the conclave (November 1550) that elected his friend, the worldly humanist and patron Pope Julius III,
Armagnac's library was constantly growing. In 1543 he commissioned an illuminated book of meditations in the best italic humanistic hand from Franc. Wydon (Musée de Condé, Chantilly) and was pleased enough with it to commission a pontifical from Wydon in 1557 (B.N.) Wherever he was, the Cardinal sought out the company of men of learning and experience, and often befriended them. When his former tutor, his countryman from Albi the adventurous philologist and investigator of the antiquities of Constantinople Pierre Gilles died penniless in Rome in 1555, Cardinal d'Aramagnac arranged from Toulouse to pay the funeral expenses and erect a wall tomb Gilles' posthumous Antiquities of Constantinople were dedicated to the Cardinal.
In 1552 he was appointed lieutenant-general of the king at Toulouse, together with the bishop of Cahors. On January 6, 1554, in the chapel of the château of Pau, he baptized Henri of Navarre, future king of France. In 1560 he was raised to the Archbishopric of Toulouse, the cultural capital of the Languedoc, the occasion for another visit to Rome.
In 1565, Pope Pius IV appointed him vice-legate at Avignon, together with the Cardinal de Bourbon. The papal city of Avignon remained faithful in the bloody Wars of Religion that had broken out in earnest in 1562, but in the surrounding Venaissin the Huguenots were solidly implanted in Orange and the neighboring Dauphiné, and fierce fighting ensued. Charles IX appointed his cousin Charles of Burgundy legate, but the man on the site was Armagnac, solidly of the Catholic party.
In this position the Cardinal d'Armagnac vigorously defended Catholic interests against the Huguenots; when his cousin Jeanne d'Albret, queen of Navarre and mother of the future Henri IV, declared for the reformed church, he sent her a stiff letter of reproof, which, with her skillful and courageous reply conjoined, was printed and circulated throughout the south. The pope showed his approval of d'Armagnac's administration by promoting him to the Archbishopric of Avignon (1576).
Georges d'Armagnac's position among the first nobility of Languedoc, his intelligence and judgment of men and events, and the protection which he granted to the arts and sciences placed him in the first rank of the faithful servants of the 16th-century Church. He was a friend and correspondent of the leading literary figures of his time in France and Italy.