He fought on the Catholic side in the French Wars of Religion; at the siege of La Rochelle, he first came to the notice of the duc d'Anjou, the future Henry III of France.
At the death of the duc de Joyeuse (1587) he was awarded the titles of Admiral of France, Governor of Normandy, of Caen, and of Le Havre.
He had not forgiven or forgotten, however, and in 1610 he was involved in the conspiracy that resulted in the assassination of Henry IV by Ravaillac, who lodged, in his preparatory visits to Paris, with Épernon's mistress, Charlotte du Tillet.
He played a large part in the immediate acceptance of Henri's widow, Marie de' Medici, as regent, her son Louis XIII being then too young to rule.
He was named military governor of Guienne in 1622, where he lived quietly for more than ten years in the Château de Cadillac.