It is practically consensual that universities contribute to economic and social growth; therefore, they nowadays need to play a more active role in answering the changing needs of society. In addition, universities hold the potential to promote regional innovation through their influence over the ecosystems they participate in. This article aims to identify, analyse and integrate the historical approaches of university ecosystems and university roles through a systematic literature review. The findings identify four different periods: (i) University-Industry collaboration (until 2000); (ii) changing the university model into a triple-helix model (2001–2010); (iii) from the triple to the quadruple-helix model in the knowledge society (2011–2020); and (iv) ecosystem complexity and the Neo Triple-Helix Model (from 2021). The study contributes to the literature on universities and the ecosystem by providing a unified perspective on the importance of the university’s role in the economic and social growth of the knowledge business and the evolution of the ecosystem. These results provide an overview of the trends in university ecosystems, including an integrative framework, research themes, and research questions able to guide future studies.