Françoise d'Issembourg d'Happoncourt was born in Nancy in the French province of Lorraine, the daughter of a military officer. In 1712, at age 16, she married François Huguet, chamberlain to the Duke of Lorraine, and the couple took the surname de Graffigny from the new estate he received from his father. They had three children but the marriage was unhappy. Madame de Graffigny obtained a legal separation from her husband, who died in 1725. She got a job as companion to an aristocrat and in 1738, they were invited to stay at the Château de Cirey, the home of Émilie du Châtelet and Voltaire, whom she knew from his trip to Lunéville in 1735.
She wrote letters during this period that were published many years later in a volume entitled La Vie privée de Voltaire et de Mme Du Châtelet (1820).
She then moved to Paris, where she wrote the epistolary novel Lettres d'une Péruvienne (1747), which made her a celebrity. She became the hostess of a salon that included the leading literary and artistic figures of the day. Among her other works was a sentimental comedy called Cénie (1750), an instant hit and one of the most successful new plays of 18th-century France.