The importance of this research stems from the need to ensure the sustainability of cross-border cooperation through a better understanding of its determinants and causal relationships. While having common features and patterns, cross-border cooperation is always expressed through the relations of specific countries and peoples. Therefore, based upon the PLS-SEM methodology, the authors consider the fundamental factors influencing the external cooperation of Hungary’s transboundary regions. The advantage of the PLS-SEM method is that it enables researchers to simultaneously identify and approximate hidden connections between input data and to construct a regression model describing the relationship between input data. Despite widespread application in economic studies, the authors have not found the use of PLS-SEM for studying cross-border cooperation issues in the current scientific literature. The authors have built a model to assess the hidden factors of cross-border cooperation and to identify the indirect influence of certain factors. The novelty of the research is to identify the determinants of sustainable cross-border cooperation and the relationship between them in a multi-level system of cross-border interaction between businesses, people, and the State. In the Hungarian context, transport infrastructure and business travel are shown to have a direct positive impact on cross-border cooperation. For the first time, tourism and socio-economic conditions have been shown to have powerful but indirect impacts. This work could be the beginning of gathering new evidence on the determinants and causation of cross-border cooperation in the context of other countries. An important finding of the study is the growing importance of indicators of the new, post-industrial economy. As for recommendations, the authors focus on state, regional, and municipal support measures, awareness of the possibilities of cross-border cooperation, the need to develop e-commerce, and alternative energy as a modern basis for converting Hungary’s cross-border position into a competitive advantage.