Lepel was first mentioned in chronicles in 1439.

In 1586 the Wilno catholic cathedra sold the estate of Lepel to Chancellor of the Great Duchy of Lithuania Lev Sapega who founded the settlement Novyi or Belyi Lepel on the south shore of Lake Lepel. It was there where the administrative and trade centre was moved to. In 1568, King Sigismund II Augustus gave the estate to Polotsk castellan Yuri Zenovich for lifetime ownership and ordered the construction of Lepel Castle. There was a port at the foot of the castle. The waterway to Riga and Kiev went through the port.

A big event in the life of Lepel which gave a boost to further growth of the town was the construction in 1797-1805 of the Berezina water system which connected the Western Dvina River basin with the Dnieper basin. 14 locks, five canals and five dams were constructed. On April 5, 1805, on the orders of Alexander I, the settlement of Lepel was awarded the status of an uyezd town.

Famous Belarusian and Polish poet Yan Chechet worked in a local school in 1833-1839.

Famous Lithuanian historian, ethnographer L. Yutsevich worked as teacher in the school for noble children in Lepel which was opened in 1830. In 1833 Lepel had one chapel, three Orthodox churches, one wooden Catholic church, four synagogues, two factories, 38 brick and 562 wooden houses.

In the early 20th century the industry of the town was represented by several small factories: a flour miller, a tobacco factory, a brewery, two cereal-making facilities, several water mills, a tar-works, a brick-works and a tannery.

The first half of the 20th century was a difficult period for the Lepel region. The region had to go through trying ordeals during the Great Patriotic War – more than 5,200 civilians were killed, 48 villages were burnt down. The Lepel region was one of the partisan movement centres during the Great Patriotic War. The region was a part of the Polotsk-Lepel partisan zone which featured 17 thousand partisans united into 16 brigades under the command of Hero of the Soviet Union V. Lobanok. The country highly valued the feat of arms of the Lepel residents. Five of them were given the high title of the Hero of the Soviet Union (I. Tuftov, N. Tomashevich, P. Yalugin, I. Erashov, V. Kvetinsky). F. Zanko is the holder of three Orders of Glory. Hundreds of local residents were awarded orders and medals.

There are 80 communal graves in the region, monuments to fellow countrymen, commemorative steles and other monuments.

The Lepel region is the birthplace of M. Kustinsky, a historian, archeologist, member of the Imperial Archeological Society; G. Bogatikov, a scientist and a holder of the doctor of biology degree; I. Zhernosek, Dr of Military Science; M. Belensky, Dr of Medicine, poets Teodor Klyashtorny, Anatoly Vertinsky and playwright P. Dudo.