The study focuses on the Angara-Yenisei macroregion, which includes four constituent territories of the Russian Federation, i.e., Krasnoyarsk Krai, Irkutsk Oblast, the Republic of Khakassia, and the Republic of Tyva. These territories are located in the zone of the Arctic latitude; areas of the Far North; areas equated to the areas of the Far North; the Southern zone, which includes the main band of population settlement. The macroregion under study is characterized by an interzonal structure of human settlement. The aim was to justify the selection of the entire macroregion and its settlement systems as an object of study. An analysis of the Angara-Yenisei macroregion based on the principle of integrity identified the need to study both its morphological and functional structural characteristics. Hierarchical clustering revealed the presence of three types of systemic zonal formations. The first type is agglomerations, which are the most dynamic elements in the structure of the territorial settlement system. The second type is represented by urban formations with cities at their core, acting as system centers and forming a supporting framework of macroregion settlement. The third type is heterogeneous, including both single-industry towns and industrial centers that are rapidly losing their population. The obtained range of quantitative assessment parameters can be used when elaborating macroregional social and economic development strategies, as well as for spatial modeling based on framework, cluster, and functional models.