Louis XII first exercised political and military power as Duke of Orléans. During Charles VIII's minority he joined the opposition to the regency of Anne of France, was captured at Saint-Aubin-du-Cormier in 1488, and remained imprisoned until 1491. Reconciled with Charles, he took part in the French invasion of Italy in 1494. He inherited the crown in 1498 and obtained the annulment of his marriage to Jeanne of France before marrying Charles's widow, Anne of Brittany, in 1499.

Louis pursued dynastic claims in Italy, capturing Milan in 1499 and recovering it after Ludovico Sforza's brief return in 1500. He agreed with Ferdinand of Aragon to divide Naples, but their armies quarreled over the conquest and France lost the kingdom. He later joined the League of Cambrai against Venice, winning at Agnadello in 1509. Pope Julius II then organized the Holy League against France, and French troops lost Milan in 1512 despite their victory at Ravenna earlier that year.

At home, Louis supported judicial reform and the recording of customary law, working closely with Cardinal Georges d'Amboise. Reduced taxation in parts of his reign helped create the reputation expressed in the title Father of the People. After Anne's death in 1514 he married Mary Tudor as part of a settlement with England. He died on January 1, 1515, without a surviving son; the crown passed to his cousin and son-in-law Francis of Angoulême.