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. Frampol lies in the area where once the village of Radzięcin existed. Its name, originally spelled Franopole, comes from Franciszka née Szczuka, the wife of count Butler. In 1735, 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. In the second half of the 18th century, the town belonged to the Wysocki family. It was an important center of artisans, mostly cloth makers, and like in other locations of eastern Poland, all houses were made of timber. Until 1795, Frampol belonged to Lublin Voivodeship, one of three regions of Lesser Poland. In 1795 - 1807 it was part of the Habsburg Empire, then it briefly belonged to the Duchy of Warsaw, which in 1815 was turned into Russian-controlled Congress Poland. In 1921, already in the Second Polish Republic, the population of Frampol was 2,720. Currently, it is one of the smallest towns in Poland.
In 1869 Frampol lost its official status as a town, to recover it only in 1993. During World War II 90% of the town's buildings were destroyed in a raid carried out by the Luftwaffe on September 13, 1939. During the German occupation the town's significant Jewish community perished in the Holocaust. The town never fully recovered - its population today is less than half of what it was before the war. Frampol, or a fictionalized version thereof, is the setting of many of the best stories of Isaac Bashevis Singer, including Gimpel the Fool.