At age eleven, Louise married Charles of Orléans, Count of Angoulême, on 16 February 1488 in Paris. She only began living with him when she was fifteen, though. Despite her husband having two mistresses, the marriage was not unhappy and they shared a love for books.
The household of Charles was presided over by his châtelaine Antoinette de Polignac, Dame de Combronde, by whom he had two illegitimate daughters, Jeanne of Angoulême and Madeleine. Antoinette became Louise's lady-in-waiting and confidante. Her children were raised alongside Louise's own. Charles had another illegitimate daughter, Souveraine, by Jeanne le Conte, who also lived in the Angoulême chateau. She would later arrange marriages for her husband's illegitimate children.
Their first child, Marguerite, was born on 11 April 1492; their second child, Francis, was born on 12 September 1494.
When her husband fell ill after going out riding in the winter of 1495, she nursed him and suffered much grief when he died on 1 January 1496.