The accumulation of knowledge that explains universities’ contributions to innovation and entrepreneurship’s regional eco-systems has mainly adopted a perspective based on technology transfer processes from academia to markets. Alternatively, in this study, we assume the notion of mutualism, based on the biomimetic rationale of eco-system studies that involve bidirectional flows of resources and capabilities to generate interactions and value co-creation among agents. This study theorizes about the interrelation between universities and eco-system actors in two directions: (a) universities fostering and improving eco-systems through their core activities; and (b) eco-system actors shaping capabilities and access to resources for universities. Based on the analysis of five eco-systems in the state of São Paulo, Brazil, our results underscore the existence of mutualism in the relationships established between universities and eco-system agents. The findings also highlighted implications related to the coordination of policies and the need for strategic management practices in mutualistic interactions.