Changes of climate and water content in the Sea of Azov and Lower Don Regions confirm the known regularities of the cyclical nature of these transformations, based on the noted instrumental observations at environmental condition after the beginning of the 18 century, and supported by more ancient historical sources. The comprehensive studies of bottom sediment columns and cores from the upper horizons of coastal spits carried out by the Southern Scientific Centre of the Russian Academy of Sciences (Rostov-on-Don, Russia) make it possible to reconstruct hydrodynamic and climatic transformations in the Sea of Azov Region in great detail during the late Holocene. The intercentury changes of climate and water content in the Sea of Azov Region were revealed according to hydrometeorological data (1884–2020), which are subdivided into three periods: cold (high-water; 1884–1942), transitional (1942–1985) and warm (low-water; 1986–2020). Lack of flood drainage and low water levels have recently led to the siltation of numerous channels and branches of the Don delta. After the regulation of the river flow (starting from 1952), the rate of sedimentation in some channels of the delta and avandelta reached 10–30 mm/year, which is significantly higher compared to the rate of accumulation of New-Azovian deposits on the shelf of the Sea of Azov (0.2 to 2.0 mm/year). An analysis of the observed patterns suggests the occurrence of the next transitional stage with abrupt interannual temperature fluctuations with alternating warm and severe winters in the next two decades.