The interesting relationship between entrepreneurial activity and regional competitiveness has been a major focus of academics, university managers, and policy makers during the past decades—in particular the role of institutions in the establishment of political, social, and economic rules-. For example, since the enactment of the US Bayh–Dole Act more than 30 years ago, many American cities and regions are increasingly viewing universities as potential engines of economic growth. In these new socioeconomic scenarios, the role of entrepreneurial universities is not only generates/transfers knowledge but also contributes/provides leadership for the creation of entrepreneurial thinking, actions, and institutions. Previous studies have shown the university’s role in economic development, but no empirical study has analyzed the entrepreneurial activity generated by university students per university at the country/regional level of analysis. The purpose of this paper is to explore the impact of the university’s entrepreneurial activity on regional competitiveness. Adopting the institutional economics and the endogenous growth approaches, a proposed conceptual framework was developed and tested with structural equation modeling using data from 102 universities located in 56 NUTS II of 12 European countries. Our results evidenced that informal factors (e.g., attitudes, role models) have a higher influence on university entrepreneurial activity than formal factors (e.g., support measures, education and training). Our results also evidenced a higher contribution of universities on regional competitiveness, in particular, when we used social measures (talent human capital) instead economic measures (GDP per capita).