In the context of digital transformation and the sustainability imperative, higher education institutions (HEIs) are increasingly positioned as orchestrators within innovation ecosystems—entities that connect knowledge production, entrepreneurship, and societal impact. This chapter offers a practice-oriented framework that analyzes how universities and business schools strategically engage in academic–industry collaboration by integrating digital infrastructures, learning analytics, and sustainability-oriented governance models. Drawing from a comparative, qualitative documentary analysis of five institutional cases across Europe and Latin America, the study identifies key enablers of academic ecosystem effectiveness, including relational infrastructure, agile co-creation governance, and digitally mediated knowledge flows. The findings reveal that HEIs can move beyond traditional knowledge transfer to actively shape entrepreneurial ecosystems but also face structural and ethical tensions that require reflexive governance. This contribution advances ecosystem theory by positioning academia not only as a participant but as a curatorial actor in the architecture of inclusive, resilient, and regionally embedded innovation systems.