The paper analyses V. N. Tatishchev’s scientific activities in 1741–1745 during his service at the Astrakhan Volga Region (Astrakhan Povolzhye) as head of the Kalmyk Commission and the Governor of Astrakhan, as well as his contribution to scientific exploration of the Lower Volga region. Based on Tatishchev’s personal documents and scientific works, it was established that the scientist was interested in geography, economic development, and history of the Lower Volga region since the 1730s although his works written before 1741 only contain fragmented and often incorrect information about the region. During the years he spent in Astrakhan, Tatishchev carried out scientific research on the region’s geography and history on his own and initiated sending to Astrakhan land surveyors and draftsmen who then conducted mapping of the region and made the first exact plans of the Golden Horde’s ancient settlements in the Lower Volga region as well as a plan and a panorama of the principal town of the governorate (guberniya). Tatishchev’s geographic works list the cities, towns, and villages in the Lower Volga region and provide information on salt extraction, wine growing, trading with Persia and India as the most promising industries in the region’s economy. In his “History of Russia,” the scientist, for the first time in historiography, provided detailed information on the annexation of Astrakhan Lower Volga region by the Russian state during the reign of Ivan the Terrible and on the actions of Don Cossacks in the Volga region during the Time of Troubles (smutnoye vremya). The manuscripts of Tatishchev’s scientific works had been known to the leading Russian scientists of the 18th century and, after these were published in the 1770s–1790s, became one of reliable sources of information on the history and geography of the Lower Volga region that had been most easily available for wide audience.