For 500 years Łuków, together with neighboring towns Siedlce and Radzyń Podlaski, was part of Lesser Poland, and was located in the extreme northeastern corner of the province.

It guarded eastern border of the Sandomierz Land, against warring tribes from the East including the Yotvingians and the Lithuanians.

In the first half of the 13th century, Łuków was the seat of Lesser Poland's castellany, positioned in a strategic corner of the province.

After prince of Kraków and Sandomierz Bolesław V the Chaste brought here the Knights Templar (1250–1257), a Roman Catholic Diocese of Łuków was established here.

In the late Middle Ages, Łuków was frequently invaded and destroyed by the Old Prussians, Yotvingians, Lithuanians, and Tatars.

In 1701, Piarist monks opened a college in Łuków, which later became one of the first in Poland to carry out the reforms of the Commission of National Education.

The discovery of the "conspiracy" by the Russians was the direct cause of the closure of the high school in Łuków and its relocation to Siedlce in 1844.

After the wave of deportations and transfers, the ghetto was rearranged as a slave labor camp for Jewish workers employed in the Gestapo warehouses.

On 4 September 1939, the German Luftwaffe bombed Łuków's train station causing many civilian deaths as a result.

Among the popular points of interest are: Łuków railway station is an important railroad junction, located on the strategic east-west line from Brest-Litovsk to Warsaw and Berlin.