Vendôme was the son of Louis de Vendôme, Duke de Mercoeur, by his marriage to Cardinal Jules Mazarin's niece, Laure Mancini. Vendôme entered the French Army in 1672 and had risen to the rank of lieutenant general by the outbreak of the War of the Grand Alliance (1689–97) between France and the other major powers. He distinguished himself in the victory over the Allies at Steenkirke (1692) and was made commander in Catalonia in 1695; two years later he captured Barcelona.

The dispute over the succession to the Spanish throne brought France and Spain to war with the British, the Austrians, and the Dutch in 1701. Appointed to the command in northern Italy in 1702, Vendôme fought the Austrian commander, Prince Eugene Of Savoy, in the bloody but indecisive Battle of Luzzara on August 15. He took Vercelli in 1704 and defeated Prince Eugene at Cassano in August 1705. In May 1706 Vendôme was transferred to the Flanders front, where the British commander John Churchill, 1st Duke of Marlborough (Marlborough, John Churchill, 1st Duke of, Marquess Of Blandford, Earl Of Marlborough, Baron Churchill Of Sandridge, Lord Churchill Of Eyemouth, Reichsfürst), had just won an overwhelming victory at Ramillies. Vendôme made limited gains until he was severely defeated by Marlborough and Prince Eugene at Oudenaarde on July 11, 1708. Vendôme subsequently failed to relieve besieged Lille (in northern France), which fell to the Allies in October. Recalled by Louis XIV, he was temporarily disgraced.

In the autumn of 1710, Vendôme was made commander of the army of King Philip V of Spain. He recaptured Madrid for Philip and on December 9 forced the British general James Stanhope to surrender at Brihuega. The next day he won a major victory over Guido von Starhemberg's Austrian forces at Villaviciosa. As a result of these triumphs, Philip was assured of his throne, and the Austrians were confined to Catalonia. Vendôme was completing the reconquest of Catalonia when he died.