In this paper, we assess the challenges of macro-universities to incorporate sustainability as an integral dimension of their activities and institutional development, and as a public higher education institutions that have an important role in sustainable development in the Global South. To this end, we analyzed the efforts oriented towards incorporating sustainability into research and teaching agendas, as well as the campus management activities of the Universidad Nacional Autónoma de México (UNAM), a university with national presence and a community of more than 420,000 people comprising students, academics and administrative staff. UNAM has historically been one of the most important research and teaching institutions in Latin America. The analysis incorporates quantitative and qualitative data, relying on information sources such as the databases of the University regarding research and teaching, institutional documents and interviews with key actors. This study argues that inter-institutional articulation is a key factor to integrate the increasing sustainable initiatives promoted in the last decade but also one of the main challenges in the consolidation of macro-universities as sustainable universities.