Epistemological approaches in classical science were grounded on the explanatory needs of the phenomena of their historical time. Nevertheless, our contemporary world shows challenging situations in which the explanatory models of normal sciences have not proved effective. One of these fields is the area of health, in which the complexity of pathological phenomena continuously overwhelms the capacity of the classical models of biomedical research to provide effective answers regarding their comprehension, prevention and control. In the last decade a new science of sustainability has emerged, grounded in general systems theory and the conceptual basis of sustainable development. This area has become a scientific possibility for transcending reductionist analyses of classical sciences, by means of systemic comprehension of contemporary phenomena within the economic, social, environmental, political and ecological domains. However, the literature shows few specific references to an epistemological approach that may establish the boundaries for a metatheoretical structure on which knowledge can be generated in the framework of this emerging scientific discipline. This paper proposes an epistemological model for analysis of the health–disease phenomenon from the point of view of sustainability science.