<p>This study uses a fuzzy-set qualitative comparative analysis of U.S. entrepreneurial innovation ecosystems. Doing so, it seeks to unveil different configurations of conditions that entail regions excelling in both high-tech entrepreneurship and innovation while paying particular attention to the role of knowledge spillovers and their respective channels. Overall, the results obtained suggest two distinct configurations, one characterized by higher knowledge creation and another characterized by higher institutional quality and entrepreneurial culture. Knowledge spillovers, talent, and venture capital are conditions found present in both main configurations. Delving into various knowledge spillover channels, the findings suggest that spillovers between unrelated or related sectors are more effective for different regions, while spillovers within sectors appear less impactful. Specialization as a channel of knowledge spillovers was found to be absent, while the cluster measure was determined to be logically redundant. These findings challenge policies promoting regional specialization and suggest a shift toward diversifying regional industrial bases. Such diversification may better support the growth of entrepreneurial innovation ecosystems.</p>