He was born in Modena, the son of Rinaldo d'Este, Duke of Modena, and Charlotte of Brunswick-Lüneburg.
During his reign, the duchy was bankrupted by the Wars of the Spanish, Polish, and Austrian Successions. As a result, Francesco was forced to sell the most precious artworks of the Estense Gallery. He was a careful administrator but most of the duchy's financial policy was in the hands of the Austrian plenipotentiary,
Among his measures, the urban renovation of Modena and the construction of the Via Vandelli, connecting the city to Tuscany.
Francesco also was the interim Governor of the Duchy of Milan between 1754 and 1771.
He died in 1780 in his villa at Varese. His son Prince Ercole succeeded him.