The object of the study was the spread of the COVID-19 pandemic in Siberia in 2020–2021. The authors examined this process with a case study of 15 federal subjects. The aim of the study is to explain the mechanism and result (in excess mortality) of penetration of the coronavirus into Siberia, based on the characteristic features of the space of Siberian regions. The novelty of the approach is the use of the most reliable monthly excess mortality statistics for characterizing the demographic impact of the pandemic, involvement of regional normative legal acts with antivirus focus, and application of the theory of spatial diffusion of innovations to describe pandemic waves in the regions of Greater Siberia. The main results of the work are as follows. First, the authors identified five types of Siberian regions in terms of integral demographic damage from the pandemic in 2020–2021: Yamalo-Nenets and Khanty-Mansi autonomous okrugs had the highest excess mortality; Omsk, Novosibirsk, Tyumen oblasts, moderately high mortality; Tomsk oblast and Altai and Krasnoyarsk krais, with relatively high mortality; Irkutsk oblast, the Altai Republic, Kemerovo oblast, the republics of Khakassia and Buryatia, and Zabaykalsky krai, excess mortality below the national average; the Tyva Republic, extremely low excess mortality for the entire pandemic. Second, the authors identified four types of regional spatial systems of Siberia according to the degree of vulnerability to coronavirus diffusion: the most vulnerable open polycentric system; highly vulnerable open centralized system; medium-vulnerable closed centralized system; the least vulnerable closed polycentric system. Third, the authors found that in the first type, the most important for the spread of the pandemic, was relocation spatial diffusion (and its particular characteristic case of rotational migrations); in the second type, relocation diffusion (“airplane”) and horizontal diffusion (in the contour of the local labor market); in the third and fourth types, horizontal spatial diffusion. The common factors of industry specialization, population density, and transport infrastructure in the conditions of Siberia had little effect on the level of coronavirus incidence. Much more important was the communication (contact-intensive) context of these factors, which determined the potential for infection and the pandemic spreading rate in the space of Siberian regions.