Economic-managerial analysis in the framework of macro-regions, multidimensional structured systems that differ in certain traditions of economic interaction, the similarity of natural and resource potential, a common production specialization and transport infrastructure, is becoming increasingly important in today’s conditions of the hierarchical public administration of the Russian economy. Counteraction to the disintegrating economic process on the basis of sustainable consolidated socioeconomic development of macro-regions is the task of the level of federal districts in this hierarchy. The study substantiates the factors of transformation of the policy of human resources reproduction in the system of strategic management of the southern macro-region in the context of the new reality. The objective of the chapter is to identify the most significant factors that form an adaptive strategy for developing the human resource potential of a macro-region to achieve sustainability benchmarks. The research methodology is based on the system-integration evolutionary-reproduction paradigm, according to which the object of management—the macro-region is considered as a dynamic multisectoral integrity that integrates the territorial entity with the functional-economic one, as a subject of socioeconomic relations and the reproduction process. The novelty of the research consists in substantiating the cluster-econometric model of analysis of transformation factors of the policy of human resources reproduction in the system of the southern macro-region strategic management in modern conditions. The result of the study is methodologically substantiated and empirically verified factors that determine the strategy for the human capital reproduction in the management system of sustainable innovative development of the southern macro-region of Russia. It is proved that in the conditions of new economic realities, the system algorithm for forming an adaptive strategy based on the identified factors should be of a cluster-econometric nature. Recommendations are formulated for economic actors for usage of the cluster-econometric model to analyze the reasons for slowing down the process of accumulating human resource potential and to develop adequate public policy measures aimed at sustainable development/increasing human capital.