Developing control systems for regional socio-economic and large technical systems is inevitably associated with the concept of human-machine complexes (HMC). They are considered as a set of a large number of hierarchically dependent complex subsystems, including staffs and machines, possessing a certain degree of organization and autonomy, interconnected by mechanisms and means of organization (i.e. material and informational links) to ensure the purposeful functioning of the entire system as a single whole in conditions of tense internal resource close to the limiting ones. The article discusses the hierarchy of interrelated homeostasis mechanisms of the HMC, ensuring both its parameter constancy and the performance of systemic functions at all hierarchy levels. In particular, the following types of homeostasis are considered: a parametric type (the internal circuit of homeostasis), designed to maintain the parameter constancy of HMC active elements and a functional type (the external circuit of homeostasis), ensuring the constancy of its functioning. At the same time, the functional integrity of the system is ensured by the work of the interrelated static-dynamic and entropy-organizational homeostasis mechanisms, which, in turn, in practical activity are implemented through coordination-motivational (CMR), organizational-motivational (OMP) and functional (FMR) mechanisms of regulation. The need for an integrated application of all entropy-organizational regulation mechanisms (CMR, OMR, FMR) in the operators’ activities determines the necessity to use multivariate methods to determine their composition and application. To solve this problem, the article examines the supersystem elements of the activity regulation, which are formed as a result of the operators’ psychological interaction in the process of their activity, as a kind of an abstract system of a higher order, which has its own supersystem properties, its own autonomous metric and conservation laws, and most importantly, its situation reflection which is different from the system one. In this case, homeostatic hierarchical networks, the elements of which are homeostatic mechanisms of HMC operators at various levels, become the basis of HMC structural-hierarchical homeostasis. Thus, being complex systems, HMC synergistically change (adapt) their internal characteristics, thereby ensure the integrity of the entire system functioning, which allows speaking, on the one hand, of their homeostaticity as the HMC most important characteristic, and on the other hand, determining the need to search for new approaches to their methodological description, and, consequently, to organizing their management and design.