The eldest son of an impoverished branch of the great family of Montesquiou, Monluc was brought up as a page at the court of Lorraine. He fought in northern Italy in 1521–22 and was with King Francis I of France at his defeat at Pavia in 1525. As lieutenant of a company he played a brilliant part in the relief of Marseille from the Holy Roman emperor Charles V's siege in 1536, and in Italy he was chiefly responsible for the great victory at Ceresole in 1544. After a period as maître de camp (“master of the camp”) in the fighting in northeastern France against the English, he became governor of Moncalieri in Piedmont in 1548 and remained in Italy for the next 10 years.

When the French Wars of Religion began in 1562, Monluc was a partisan of the Roman Catholic house of Guise. His victory at Vergt (Oct. 9, 1562) broke the Huguenot power in Guyenne, and he later became a powerful force within the league of Roman Catholic nobles in the southwest. Huguenot propaganda gave him a reputation for barbarity that he did not deserve.

In his Commentaires (1592; Eng. trans., 1674), he records his successes with frankness, but he does not conceal his mistakes. Militarily he stood for the use of mobile infantry (notably harquebusiers) against cavalry.