This article states the need to decolonize the theories, policies, and practices that dominate health, and reflects on the necessity for a new epistemology built from the Global South. This allows rethinking health with a new categorical framework, which incorporates socially determined health and life, with the optic of reaching the highest conceivable degree of living well/well-living. We put forth that the epistemic bases of epidemiology and the implementation of health systems tend to reproduce a coloniality of power and of established health knowledge. Health systems are viewed as an accumulation of reforms based on theories and policies of the Global North imposed on Latin America and the Caribbean. These systems have been built as bureaucratic, biomedicalized, treatment-oriented, and commercialized health systems that are perceived as external to societies and that reproduce mistreatment, violence, and racism. We make the argument to rethink, remake, and decolonize the theories and practices that govern both epidemiology and health systems, and, from the South, develop strategic processes for building health sovereignty as the vision for the reconstruction of hope and social justice.