The only son of Louis XI and Charlotte of Savoy, Charles showed no aptitude for government at the time of his accession: he was in poor health and of poor intelligence. Though he was legally of age, the government in the first years of his reign was in the hands of a regency comprising his sister Anne and her husband Pierre de Bourbon, seigneur de Beaujeu. After his marriage to Anne of Brittany in 1491, however, Charles was persuaded by his favourite, Étienne de Vesc, to free himself from the Beaujeus. By his Breton marriage Charles forfeited rights to Artois and the Franche-Comté that he had acquired by his engagement to Margaret of Austria, and he also agreed in the Treaty of Étaples (1492) to pay heavy compensation to King Henry VII of England for the abandonment of English interests in Brittany. Furthermore, in 1493, by the Treaty of Barcelona, he ceded Roussillon and Cerdagne back to Aragon.

The motive for these cessions was to free his hands for his grand enterprise, an expedition to Italy to assert the right to the kingdom of Naples that he had inherited from the Angevins. This absurd ambition inaugurated a series of Italian wars lasting more than 50 years and gaining the French kings only momentary glory in return for a vast outlay of men and money. Having borrowed money left and right to raise a great army, Charles crossed Italy unopposed in 1494 without suspecting that he was leaving enemies behind him. Charles entered Naples in triumph on Feb. 22, 1495, and was crowned there on May 12, but already the opposition of Milan, Austria, Venice, and the Pope was rallying against him. He escaped with difficulty from the Battle of Fornovo and had lost his conquests by the time he returned to France. He died while preparing for another expedition.