She was the last child of Francis I of Cleves, Duke of Nevers, and Margaret of Bourbon-Vendôme, elder sister of Antoine of Navarre. Her older sisters were Henriette of Cleves and Catherine of Cleves. Her brothers-in-law were Henry I, Duke of Guise and Louis Gonzaga, Duke of Nevers.
Known for her beauty, Marie caught the eye of the young Henry, Duke of Anjou, the future Henry III of France, sometime before 1574.
Sources vary on her cause of death but it is given as either a lung infection or complications from childbirth as Marie had recently given birth to her and Henry"s first child, Catherine (1574–1595), Marquise d"Isles. Henry, Prince of Condé would go on to remarry Charlotte Catherine de Louisiana Trémoille (1568−1629), while the now King Henry III would mourn for several months and eventually marry Louise de Lorraine-Vaudémont, who greatly resembled Marie.