Important cities within the region include Vitebsk, Orsha, Polotsk, and Novopolotsk.

Vitebsk region covers an area of 40,000 km²,[4] which is about 19.4% of the national total.

The northern extreme point of Belarus is situated in Verkhnyadzvinsk District of Vitebsk region, north of Lake Osveya.

[5] In 2000 Belarusian scientists Alexey Solomonov and Valery Anoshko published a report in which they stated that the geographic centre of Europe was located near Lake Sho (Belarusian: Шо) in the Vitebsk region.

Other lakes are Beloye, Nescherdo, Snudy, Lisno, Ezerische, Strusto, Richi, Losvido and Lepelskoye.

Braslav Lakes and Naroch National Parks and Berezinski Biosphere Reserve comprise 3,4% of the whole region's territory, and 22 wildlife preserves of national importance make up 4,1% of the region.

Vitebsk region has a number of important transport connections with Russia, Ukraine, the Baltic countries, and Poland.