In 1542, King Sigismund II Augustus granted town charter to Siemiatycze, and with the 1569 Union of Lublin, it passed to the Kingdom of Poland within the Polish–Lithuanian Commonwealth.

The town, conveniently located along the Bug River, and near local administrative centers at Drohiczyn and Mielnik, became a popular market place, where farmers sold their produce.

The town continued to prosper, at the expense of other municipalities of the region of Podlachia, some of which were burned to the ground by the Swedish, Transilvanian and Russian invaders.

During the joint German-Soviet invasion of Poland, which started World War II in September 1939, Siemiatycze was invaded by Germany, which then handed it over to the Soviets in accordance with the Molotov–Ribbentrop Pact.

Siemiatycze was to a large extent destroyed during the war, and its significant Jewish community was almost completely exterminated by the Nazis (with the help of the local Poles) in the Holocaust, although a few Jews survived by paying their neighbors to hide them.