Despite the increasing scientific literature on innovation and entrepreneurship in the academic setting, the literature is still fragmented and broadly conceptualized, requiring more systematic and holistic studies. Furthermore, few studies have been identified from the perspective of systemism, in which both individual agency and structure are involved in a given context. This chapter aims to explore innovation and entrepreneurship in the academic setting from the approach of complex systems. It tries to understand how innovation and entrepreneurship support universities to contribute to regional socio-economic development while preserving their own sustainability. Methodologically, an exploratory and descriptive multiple case study was conducted considering four universities in two different regions and countries: Catalonia in Spain (Universitat Autònoma de Barcelona, UAB; and University of Barcelona, UB) and Rio Grande do Sul in Brazil (Pontifical Catholic University of Rio Grande do Sul, PUC-RS; and University of Vale do Rio dos Sinos, UNISINOS). Interviews, documents and direct observation were used as data sources. The main findings indicate a system composed of individuals and artefacts at a micro level and an academic and a management organization at macro-level. The systems structure is defined at individual, organization and interaction levels. Mechanisms are related to teaching, research, extension and management functions. The chapter makes both theoretical and practical contributions. From the conceptual point of view this chapter includes a unique discussion related to modelling universities as social systems in the context of the knowledge-based society from the perspective of complex systems. From the practical perspective, the chapter includes the fact that finding mechanisms not only allows an understanding of the system, but also the possibility to control it.