Global prevention efforts, including mitigating the Covid-19 impact, require a more serious mechanism, such as maintaining sustainable regional development security. This research examines the role of social entrepreneurship collaboration with institutions in maintaining sustainable regional development security using empirical data and path analysis. To measure sustainability, sustainable entrepreneurship business opportunities are used as an aspect of sustainable regional development. The results show that the new model innovation of social entrepreneurship collaboration and institutional quality is an important mechanism capable of optimizing resource use, overcoming socio-economic problems and poverty, and increasing productivity. Furthermore, it is a value chain in promoting public policy implementation and mitigating sustainable regional development security. Since the new model innovation creates better social and economic justice values, it is the most important innovation element in the basic framework of social innovation sustainability theory.