The town was founded in 1717 by Count Marek Antoni Butler, with a unique, highly symmetric layout of streets in the shape of concentric rectangles around a large central square.

Its name, originally spelled Franopole, comes from Franciszka née Szczuka, the wife of Count Butler.

In 1735, the Jewish community of Frampol already had its own cemetery, and in 1740, Józef Butler funded a wooden church, which since 1778 exists as a separate parish.

During the German invasion of Poland at the start of World War II, 90% of the town's buildings were destroyed in a raid carried out by the Luftwaffe on September 13, 1939.

Frampol, or a fictionalized version thereof, is the setting of many of the best stories of Isaac Bashevis Singer, including Gimpel the Fool.