This paper explores the use of systems theory to inform the mainstreaming of sustainability in a university's functions as it responds to sustainable development challenges in its local context. Offering a case study of Rhodes University, the paper shows how the use of systems models and concepts, underpinned by a critical realist ontology and an understanding of morphogenetic change processes, have the potential to enable universities to mobilise their operations to respond to local sustainability challenges. In this instance, the success of such an approach is shown to depend on commitments from the university community and the availability of enabling inputs, such as financial and human resources. The paper concludes with reflections and recommendations to inform further development of a newly emerging systems approach in sustainability mainstreaming at Rhodes University, and other institutions pursuing similar approaches and goals.