To combat foreign invaders, a new state was formed in the 13th century – the Grand Duchy of Lithuania, Ruthenia, and Samogitia. By the end of the 13th – beginning of the 14th centuries, most Belarusian lands became part of it, including the principalities of Vitebsk, Polotsk, Lukoml, and Druck.

In the 15th-16th centuries, Polotsk and Vitebsk were significant trading and cultural centers. Trade was conducted not only with other territories of the Grand Duchy of Lithuania but also with Germany, Bohemia, Italy, Hungary, the Muscovite states, and others.

The unification of Belarusian lands within the Grand Duchy of Lithuania played a crucial role in the formation of the Belarusian ethnos. The Belarusian language, folk clothing, and the distinctiveness of folk life were being shaped.

Polotsk gave the world culture the great F. Skaryna (circa 1490 – 1551). He is known as a humanist, a pioneer printer, and the author of prefaces and epilogues to the books he published, which were always adorned with engravings.

Architecture also developed intensively during this period. It combined the traditions of Belarusian architecture of the 11th-13th centuries with the influence of Western European architecture. During this time, primarily fortresses and castles, palaces, and religious buildings were constructed. The most powerful fortresses were built in Vitebsk and Polotsk.

Princely palaces and churches began to be decorated with frescoes. Graphic arts were widely developed, and books were adorned with miniatures and headpieces depicting historical and battle scenes, as well as portraits of famous saints and princes. The Orsha Gospel is considered a model of such book design.

In the early 16th century, the principalities of Vitebsk ceased to exist. As a result of the administrative-territorial reform of the Grand Duchy of Lithuania, the Polotsk Voivodeship was established in 1504, and the Vitebsk Voivodeship in 1508.

Despite wars and periodic exacerbation of relations with neighboring states, in the late 16th – 17th centuries, Vitebsk continued to be a major administrative, craft, and trading center of the voivodeship, with a population of about 10,000 inhabitants. The city had a developed education system. Starting from the 16th century, schools operated at Orthodox, Catholic, and later Protestant churches and monasteries.

In 1498, Polotsk, and in 1597, Vitebsk received Magdeburg rights. In 1620, these rights were granted to Orsha. Magdeburg rights enabled Polotsk and Vitebsk to have their own coats of arms.

The population of the Vitebsk region was predominantly Orthodox.
The inclusion of the Vitebsk lands into the Polish-Lithuanian Commonwealth led to the spread of Catholicism. Churches began to be built, and Catholic monasteries appeared. In 1629, the parish (Dominican) church operated in Vitebsk, in 1676 the Bernardine monastery with St. Anthony's Church was built. In 1682, the Vitebsk Jesuit Collegium was opened.

In the 16th century, Orsha became a major religious and cultural center. In opposition to Catholic expansion, Orthodox brotherhoods began to operate in the Orsha region from 1592. Famous woodcarvers, engravers, jewelers, chasers, and gunsmiths worked in the Orsha region.

In Polotsk during this period, the Bernardine monastery, as well as Uniate and Orthodox monasteries, were active. In 1581, the Polotsk Jesuit Collegium was founded, which housed the Polotsk printing house. After the adoption of the Union of Brest, the Polotsk Saint Sophia Cathedral became the Uniate cathedral.

In 1796, by merging the Mogilev and Pskov provinces and the Polotsk vicegerency, the Belarusian Governorate was created with its center in Vitebsk, and in 1802, the Vitebsk Governorate was established.

The placement of the residence of the Belarusian Governor-General in Vitebsk, and later its designation as the center of the newly created governorate, was of great importance for the city's development. By the second half of the 18th century, it had become the second largest city in Belarus (after Mogilev). In 1777, the first industrial enterprise, a tannery, began operating in the city; later, tile, rope, and lime factories emerged.

The Vitebsk Governorate printing house operated from 1797.
The inclusion of the Vitebsk region into the all-Russian market system, thanks to the location of several cities, particularly Vitebsk, on the banks of the Western Dvina River, was of great importance for the growth and development of the lands of the Vitebsk region as a whole.

The Vitebsk region endured severe trials during the Patriotic War of 1812, when fierce battles took place on its territory.

According to the census of 1897, Vitebsk, the center of the governorate, had a population of 65,871 residents. In 1866, the Riga-Oryol railway was laid through the city, and later railway lines connected the city with Moscow, St. Petersburg, Kyiv, and Brest.

The major cities of the Vitebsk Governorate during this period were Vitebsk, Polotsk, and Orsha.

The public life of the Vitebsk region in the 19th century was influenced by the ideas of the liberation movement. I.I. Gorbachevsky (a future Decembrist), who graduated from Vitebsk Gymnasium, spent his youth in Vitebsk. N.M. Muravyov, one of the organizers of the Decembrist "Northern Society," lived in the city from May to October 1821. The Decembrist A.A. Bestuzhev-Marlinsky served in Polotsk and Beshenkovichi. The revolutionary I.V. Babushkin lived in Polotsk from September 1900 to the spring of 1901.

The population participated in the First Russian Revolution of 1905-1907. In 1905, solidarity strikes with the workers of Moscow took place in Vitebsk, Polotsk, Orsha, and other cities and towns of the province.

On the eve of World War I, Vitebsk had a population of 109,000. The city continued to be one of the largest industrial centers of the Western Krai, with 45 factories and plants employing about 8,000 people. News of the February Revolution events in the province became known in early March 1917. Soviets were established in the Polotsk and Drissa districts on March 7, in the city of Polotsk on March 15, and in the city of Vitebsk on March 20.

From December 10-17, 1917, the I Extraordinary Congress of the Vitebsk Provincial Soviet of Workers', Soldiers', Peasants', and Batraks' Deputies was held, which legally consolidated Soviet power in the Vitebsk province and elected the provincial executive committee.

In connection with the creation of the Lithuanian-Belarusian SSR (February 1919) and the occupation of part of Belarus by Polish troops (February-August 1919), the Vitebsk province was transferred to the RSFSR.

Despite all the hardships of the war, by the early 1920s, the city had become a major cultural center. As early as 1918, a symphony orchestra and a people's conservatory were organized in Vitebsk. At the initiative of the artist Marc Chagall, a people's art school (later renamed Vitebsk Art College) was opened, and the Vitebsk Provincial Museum and a state art and decorative workshop were founded. Such famous artists and philosophers as K.L. Boguslavskaya, M.V. Dobuzhinsky, V.M. Ermolaeva, K.S. Malevich, I.A. Puni, M.M. Bakhtin, and many others lived and worked in the city. There were 3 theaters, 6 clubs, and cinemas operating, etc.

In 1926-1928, the industry of Belarus developed at a faster pace than before. In 1927, there were 36 industrial enterprises in Vitebsk alone, employing 7,036 workers. Among them were the "Dvina" flax-spinning mill, the "Profintern" sewing factory, the K. Zetkin hosiery factory, and the "Krasny Metallist" plant.

Y. Kupala, Y. Kolas, K. Cherny were frequent guests in the Vitebsk region. The city of Vitebsk was visited by A. Tolstoy (1924), V. Mayakovsky (1927), and other famous writers.

Before the Great Patriotic War, about 40% of the republic's entire processing and textile industry was concentrated in the region.

On the eve of the war, Vitebsk was also the largest cultural center of the region.

On July 11, 1941, Vitebsk was occupied.

From the first days of the occupation, in the Surazh district, the detachment of Batka Minay (M.F. Shmyrev), created in July 1941, waged a ruthless struggle against the enemy. During the same period, the detachment of "Uncle Kostya" (K.S. Zaslonov), formed on the basis of a group operating in the Orsha underground, began its activities. V.Z. Khoruzhaya, E.S. Zenkova, who were awarded the title of Hero of the Soviet Union (Khoruzhaya - posthumously), I.A. Bekishev, A.E. Belokhvostikova, T.A. Marudov, and others became a bright page in the history of the Vitebsk underground.

The liberation of the region began in the autumn of 1943 and continued in the summer of 1944 during Operation Bagration. On June 26, 1944, Vitebsk was liberated.

During the war years, Vitebsk, Polotsk, and Glubokoye suffered the greatest human losses. Of the 180,000 people who lived in Vitebsk in 1940, only 118 residents remained after the expulsion of the occupiers. The city was destroyed by more than 93%.

In 1967, for active participation in the partisan movement, courage and heroism of the working people during the Great Patriotic War, for successes in the restoration and development of the national economy, the region was awarded the Order of Lenin, the city of Vitebsk - the Order of the Red Banner of Labor (1974), Orsha - the Order of the Patriotic War, 1st degree (1984).

In the 1960s-1970s, many large modern factories were built in the region: color televisions, protein-vitamin concentrates, "Evistor", "Stekl fiber", expanded clay gravel, the "Zarya" furniture factory, the Vitebsk House-Building Combine, production associations "Naftan", "Polimir", "Monolit", "Electroizmeritel", "OrshaStroymaterialy" and many others. New cities appeared on the region's map, becoming major industrial centers of Belarus: Novopolotsk and Novolukoml.

Currently, Vitebsk region is a highly developed industrial and agricultural region, widely known for its spiritual and cultural traditions.