The study was carried out on the most relevant topic of the current stage of the development of the domestic economy. In a dynamically changing international environment, large socio-economic systems encounter insurmountable obstacles that represent a set of organizational and economic problems. Their resolution requires a lot of attention and prompt response. The material of the article is aimed at revealing the capabilities of large socio-economic systems to overcome organizational and economic problems caused by uncertainty in the macroeconomic environment. The article considers the features of the formation of organizational and economic problems and identifies the conditions for overcoming them by complex socio-economic systems. To identify organizational and economic problems on the path of development of large socio-economic systems, the study uses methods of generalization, grouping of available information about changes in the macroeconomic environment, as well as methods of induction and system analysis to find rational solutions. The conducted research reflects the author's position on the implementation of anti-crisis management measures of natural monopolies. This object was not chosen by chance. It is precisely such enterprises that concentrate the interests of the development of the state, the market and society as a whole. The activity of each of them, the author proves, is an independent regulator of market relations for a particular region. The factors of the crisis situation of complex socio-economic systems are macroeconomic conditions that violate the order of provision, production and organization of sales of natural monopolies. At the same time, a set of problems can dictate both private decisions on the formation of measures for the alternative use of the property complex, and radical solutions affecting all types of activity of a natural monopoly entity. The choice of a specific way to resolve organizational and economic problems requires the construction of a management solution aimed at resolving the crisis situation. The article develops the author's algorithm for making managerial decisions to overcome organizational and economic problems of a large socio-economic system caused by uncertainty at the macroeconomic level. Such problems have affected the activities of many socio-economic systems in various sectors of management. It is emphasized that low flexibility in the implementation of core activities makes the largest socio-economic systems the most risky and unprotected enterprises, unable to adapt and implement alternative discrete-time projects.