The central research question of this paper is how a regional or national (spatial) innovation and entrepreneurial ecosystem (SIEES) can function in a sustainable mode under conditions of uncertainty of an external environment. As an attempt to answer this question, the authors consider to approach the idea of sustainable development from the standpoint of a nonlinear dynamic stability of open systems through information exchange. Addressing this issue as a multi-criteria decision problem, the authors integrate the concept of the “Innovative Helix” and its modifications, which are describing the interaction of science, government and business, as well as formal methods of game theory and business simulation games as a basis for modeling the process of sustainable development in a spatial innovation and entrepreneurial ecosystem. The purpose and interest of the article is to provide input for further discussion on these and other issues related to organizing and governing the interaction of key stakeholders in such arrangements. In practical terms, also a first case study for Russia will be designed and set up for further discussion.