His mother, pious and rigorous, served as his regent until 1674, filling state offices with clerics under the advice of her Jesuit confessor Father Garimberti.

His character changed dramatically in the free and easy company of his cousin, principe Cesare Ignazio d'Este, and after her return the dowager duchess withdrew from court.

Francesco's foreign policy was affected by the requirements of Louis XIV, his sister's patron after 1688, but he resisted French attempts to interfere in the duchies.

A Franco Modenese alliance was proposed with Francesco and a princess of the House of Lorraine, Béatrice Hiéronyme, the eldest daughter of François Marie, Prince of Lillebonne.

The couple had no children and when Francesco died heirless in 1694 after just two years of marriage, he was succeeded by his half-uncle Cardinal Rinaldo d'Este, who renounced his ecclesiastical career and cardinalate for this purpose.