The Sukhaya Mechetka is the most important Middle Paleolithic site in the Eastern Europe. The paper presents the analysis of the section, including its cultural layer, in the context of stratigraphy and paleogeography of the Lower Volga River region. The structure of the section represents 11 main stages of sedimentation and paleogeographic evolution of the site territory, which are closely related to global and regional changes in the climate and the level of the Caspian Sea. The base of the section reflects the stage of a river existence on the territory of the site that flowed into the Volga River estuary, formed by the Early Khazarian transgression of the Caspian Sea at the end of the Middle Pleistocene (MIS 6). A long continental period of evolution under multi-directional climate fluctuations of different amplitudes from the Mikulino interglacial (MIS 5e) till the Late Valdai glacial epoch (MIS 2) is reflected in the middle part of the section. The Late Khazarian and Hyrcanian transgressive basins (MIS 5), as well as the Paleo-Khvalynian stage (MIS 3) of the Caspian Sea did not reach the latitude of Sukhaya Mechetka. The stage of Early Khvalynian transgression (MIS 2, 16 190 ± 200 years ago) during the degradation of Ostashkovo glaciation is expressed in the upper part of the section. Three paleosoils have been found that reflect the warming periods of the MIS 5 stage and are related to its 5e, 5c and 5a sub-stages. The middle paleosoil contains a cultural layer assigned to the Micoquian/KMG community of Northern Eurasia. The climate was moderately warm during the Neanderthal settlement of the territory, steppe landscapes dominated the interfluve, and the forests grew in the balka. The Hyrcanian transgression of the Caspian Sea with an estuary in the Volga River valley predetermined a high erosion basis and the formation of a balka with a wide bottom and gentle banks. A permanent fresh watercourse attracted mammals which were an object of hunting for ancient men. All this, obviously, became a basis for the organization of settlement in the Sukhaya Mechetka balka. Correlation of the section with detailed studied loess-soil sections of the Lower Volga River region makes it possible to determine the age of its cultural horizon in between 97-110 thousand years ago.