He was elected archbishop of Reims in 1574, succeeding his uncle, Charles of Guise. On 21 February 1578, he was created cardinal; he took the title of Cardinal of Guise, succeeding his uncle, Louis I, Cardinal of Guise. He was later named papal legate to Avignon, and made by Henry III of France a knight of the Order of Saint Esprit.
His dedication to the cause of his brother Henry I, Duke of Guise, and intransigence to the royal power provoked the hostility of Henry III. At the royal command, the Cardinal was assassinated at the Château de Blois by the King's bodyguard known as "the Forty-five", the day after his brother.
Louis had an illegitimate son:
- Louis bâtard de Guise (1588–1631), born of his liaison with Aimerie de Lescheraine, dame de Grimaucourt, was legitimised in 1610, after his father's death. Louis became prince of Lexin and married Henriette de Lorraine, daughter of Francis II, Duke of Lorraine.
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