He was a son of René of Savoy and Anne of Lascaris. He accompanied Henry II of France on his 1552 trip to Lorraine and in 1553 relieved the town of Hesdin from its siege by the prince of Piedmont. He was wounded at battle of Saint-Quentin on 10 August 1557, though this did not stop him relieving Corbie from its Spanish siege. He accompanied Charles IX of France on his grand tour of France and in 1567 assisted at the Assemblée des Grands de France held at Moulins. He fought zealously against the Huguenots, fighting at Saint-Denis and Moncontour.
In 1540 he married Jeanne Françoise de Foix, viscountess of Castillon (†1542), with whom he only had one child, Henriette de Savoie-Villars († 1611), who married Charles, Duke of Mayenne. In 1565, his fiefdom of Villars was promoted to a marquisate dependent on the House of Savoy. In 1570, he succeeded Blaise de Monluc as lieutenant of Guyenne, where he repressed the Huguenots in 1573. The king rewarded him by making him marshal of France in 1571 and admiral of France and of the Levant Seas in 1572 after the death of Gaspard II de Coligny. He was dismissed as admiral in 1578 in favour of his relation Charles de Lorraine, duc de Mayenne. He was appointed to the Order of the Holy Spirit on 1 January 1579.