For many years, the Department for Regional Development Modeling and Forecasting at the Institute of Economics KarRC RAS, together with scientists from Petrozavodsk State University, University of Eastern Finland and medical institutions, has been conducting comprehensive research at the intersection of economics, demography, medicine and ecology. The studies were supported by ten grants from the Russian Foundation for Basic Research and Russian Foundation for the Humanities. This article examines the effect of the COVID-19 pandemic on mortality in Russian regions. The purpose of the study is to identify factors that have significantly raised mortality rates in Russian regions during the pandemic. The impact of socio-economic, demographic, medical, and geographical variables on morbidity and mortality rates in different stages of the pandemic was assessed taking into account regional characteristics. It is shown that, in general, mortality was promoted by higher shares of retirees and urban population, the location of the region in the center of the country, and a drop in citizens’ incomes in 2020 (compared to 2019). The first (spring) wave of the pandemic in Russia was relatively low, largely due to the imposed heavy restrictions. As a result, only in some months did the lower availability of hospital beds in a region contribute to higher mortality. The highest increase in mortality rates happened in regions of the Central Federal District. During the summer period, the incidence decreased and restrictions were relaxed, but increased mobility of people led to an increase in mortality in regions of the Volga Federal District, which are situated along the main roads and railways. By the end of the summer, the availability of doctors and hospital beds in the region became significant factors for increase in mortality, in addition to the three main indicators. In the fall, the second wave began, during which the increase in mortality depended on the location of the region, the proportion of the urban population, and the availability of doctors in the region. In some months, the level of income of the population and its change in 2020 had a significant effect. In December, the situation in the Volga Federal District and the Siberian Federal District stabilized, while mortality rates in southern regions of the country began to grow. The study was carried out by researchers from the Institute of Economics KarRC RAS and the Republican Infectious Diseases Hospital, and its results can be used to aid decision-making and safeguard the health of the nation through the regional medical and demographic policy.