The aim of the chapter was to model the impact of selected determinants (trade openness, human capital, entrepreneurship, and innovation) on regional competitiveness, as well as to propose future activities and measures required to be implemented to improve the competitive performance of the regions. The research was conducted on the sample of 18 regions in six European countries: Serbia, Croatia, Slovenia, Northern Macedonia, Montenegro, and Romania. The database was prepared, and the statistical processing was performed in SPSS. In this data analysis, the following methods were used: comparative analysis, correlation, and regression analysis. The results of the research showed that the impact of the determinants—import dependence, the number of pupils enrolled in secondary education, gross domestic expenditure on research and development, and the number of companies per 10,000 inhabitants on the competitiveness of the region—are (statistically) significant.