After completing his education, he became a protonotary apostolic. He also became a canon of the cathedral chapter of Bordeaux Cathedral. He was next the Prior of the Priory of Saint-Martin-des-Champs.
Following the death of Louis XI of France in 1483, he traveled to Brittany to serve Charles VIII of France. He attended the Assembly of the French clergy in 1485. Under Charles VIII, he served as governor of Paris. On October 1, 1488, he was named Archbishop of Lyon, occupying that see until his death, while also retaining the metropolitan see of Bordeaux.
At the request of Charles VIII, Pope Innocent VIII made Espinay a cardinal priest in the consistory of March 9, 1489. He received the red hat and the titular church of San Martino ai Monti on March 23, 1489.
He did not participate in the papal conclave of 1492 that elected Pope Alexander VI. On November 1, 1492, the new pope named him papal legate to Charles VIII of France. As such, the cardinal accompanied Charles VIII on his campaigns during the Italian War of 1494–1498, and was close to the king during the 1495 Battle of Fornovo.