BackgroundCountries have adopted different COVID-19 policies to contain the transmission of the disease and to prepare for vaccination rollout. Countries’ political context, vaccine policy history, and health systems’ responses impacted COVID-19 health outcomes. ObjectiveThis study focused on synthesizing and examining COVID-19 non-pharmaceutical interventions in Brazil and Portugal, understanding the enablers and barriers to COVID-19 vaccination access and distribution, and health and non-health outcomes across three time-points: before vaccination, during mass vaccination, and after the declaration of endemicity. MethodsExtensive qualitative document analysis of secondary sources published in Portuguese and English over the past three years, and examination of primary publicly available epidemiological data since the beginning of the pandemic. ResultsIn the first year of the pandemic, the COVID-19 government response between the two countries was dissimilar; effective coordination, trust in the government response and political alignment in Portugal contrasted the political denial of the pandemic, lack of coordination between the various levels of government, at the same time the Brazilian population engaged in protective behaviours and distrusted the government. The COVID-19 vaccination had a good response from the public, associated with a primary care level network of distribution, low vaccine hesitancy, and strong childhood immunization programs before the pandemic in both countries. Vaccine manufacturing in Brazil and the strong support from the European Union to Portugal on vaccine acquisition have also aided these countries in achieving high COVID-19 vaccination coverage. ConclusionFuture policies to promote a well-functioning and resilient health system should consider medical and nursing workforce sustainability, equity in all policies, building public trust, strengthening health system governance, and improving preparedness and surveillance.