[6] This region comprised the westernmost "borderlands" of the early East Slavs (possibly the tribal union Dregoviches) on the lands of the Balts in the 6th–9th centuries CE.

[8] The Baltic Yotvingians who inhabited the Grodno region became increasingly Lithuanized, especially during the formation of the State of Lithuania in the 13th century.

Historical cities of notable importance were Grodno (seat of Grodno County and one of the main royal residences of the Polish-Lithuanian Commonwealth), Nowogródek (provincial capital since 1507), county seats of Vawkavysk, Slonim, Lida, and Mir, (a private town of the Radziwiłł family).

[10] The strong economic development of the area continued during the reign of Casimir's son — Duke Alexander Jagiellon of Lithuania (r. 1492–1506) — who founded the first solid bridge over the Neman River, as well as the monasteries of the Order of Saint Augustine and of the Polish Order of Friars Minor.

During his reign, Grodno became a royal headquarters and began to host sessions of the Polish–Lithuanian Commonwealth Senate and Parliament (Sejm).

In 1580, on the king's order, the castle of Grodno was rebuilt in Renaissance architectural style by Scoto di Parma.

Deterioration of the province's status began with the Livonian War between 1558 and 1583, which pitted the Polish–Lithuanian Commonwealth and the Swedish Empire in a lengthy and exhausting military conflict against the Tsardom of Russia.

As part of the Polish-Lithuanian Commonwealth, and due to subsequent Partitions of Poland, the whole of the Grodno region was annexed by the Russian Empire by the end of 1795.

Towards the end of the war, the Belarusian People's Republic (BNR) declared its independence from Soviet Russia in March 1918 in Minsk.

Under the terms of the Peace Treaty of Riga, the region and the city returned to the Second Polish Republic which claimed rights to this territory as a successor to the Polish–Lithuanian Commonwealth and as a victorious side of the Polish–Soviet War.

In 1942, after a year of severe persecution and planned starvation of ghetto inhabitants, 10,000 Jews from Grodno were deported to the German concentration camp of Auschwitz-Birkenau to be killed.

As of 13 March 1943, German troops reported the completion of the extermination and declared Grodno city judenfrei (free of Jews).

As a result of Joseph Stalin's policy of expansion to the west, it was decided (during the Yalta Conference) that the Polish eastern border would be set roughly along the Curzon Line.

When the so-called "mistake" (today regarded rather as sabotage within British ministry structures) became obvious to negotiators, Stalin refused to correct the mistaken line.

The main tourist attractions in the region are numerous old architectural constructions such as castles in Mir, Lida, and Novogrudok.

The Mir Castle Complex and Belovezhskaya Pushcha National Park are UNESCO World Heritage Sites.

There are a number on national minority associations: 6 Polish, 6 Lithuanian, 4 Jewish, 1 Ukrainian, 1 Russian, 1 Tatar, 1 Georgian, 1 Chuvash.