The article analyzes the fight against COVID-19 in three Latin American countries: Argentina, Brazil, and Mexico. A multiple case study was carried out in a comparative perspective, based on a bibliographic review, documentary analysis, and secondary data, considering characteristics of the countries and the health system, evolution of COVID-19, national governance, containment and mitigation measures, health systems response, constraints, positive aspects and limits of responses. The three countries had distinct health systems but were marked by insufficient funding and inequalities when hit by the pandemic and recorded high-COVID-19 mortality. Structural, institutional, and political factors influenced national responses. In Argentina, national leadership and intergovernmental political agreements favored the initial adoption of centralized control measures, which were not sustained. In Brazil, there were limits in national coordination and leadership related to the President's denialism and federative, political, and expert conflicts, despite a universal health system with intergovernmental commissions and participatory councils, which were little used during the pandemic. In Mexico, structural difficulties were associated with the Federal Government's initial reluctance to adopt restrictive measures, limits on testing, and relative slowness in immunization. In conclusion, facing health emergencies requires strengthening public health systems associated with federative, intersectoral, and civil society coordination mechanisms and effective global solidarity mechanisms.