The coronavirus disease 2019 (COVID-19) pandemic, produced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly throughout the world. Latin American and the Caribbean countries have been harshly affected by the pandemic mainly due to less prepared healthcare systems and fragmented social safety nets. In the region, health status population-based indicators are worse than compared to the Organization for Economic Cooperation and Development. Recent evidence suggests that the progression and severity of COVID-19 are associated with the prior health status of individuals, and studies have shown that the case fatality rate is highly stratified among different populations. This narrative review aims to describe factors associated with adverse outcomes of COVID-19 in the context of social determinants of health in Latin American and Caribbean countries. In this review, we state that genetic and biological factors interact in a sophisticated way with social determinants of health, impacting the rapid spread of COVID-19 in Latin American and Caribbean countries. Behavioral factors, such as physical inactivity, smoking, and unhealthy diets, are related to chronic systemic inflammation. Also, air pollution can prolong inflammation and the hyper-activation of the immune system. Air pollutants could facilitate the spread of the virus. Finally, frailty and comorbidities can be associated with COVID-19 severity through increasing vulnerability to stressors and leading to more severe symptoms of COVID-19 disease, including a higher mortality risk. All these factors contribute to increasing the impact of COVID-19 in Latin American and Caribbean countries. We highlight the relevance of considering social determinants of health in Latin American and the Caribbean countries, not only in controlling the likelihood of getting the disease but also its progression and severity. All these social determinants can guide the design and implementation of tailored interventions promoting healthy lifestyle behaviors, which should lower the spread of the disease, its severity, and lethality.