The burden of coronavirus disease (COVID-19) in sub-Saharan Africa (SSA) has been substantially lower compared to other regions of the world. Extensive morbidity and mortality were not observed among countries in SSA during the first wave of the COVID-19 pandemic. To explain this phenomenon, several hypotheses have been formulated, including the low median age of the population in most SSA countries, lack of long-term care facilities, cross-protection from other local coronaviruses, insufficient testing and reporting resulting in an undercounting of COVID-related deaths, genetic risk factors, or the benefit of early lockdowns that were extensive in many SSA countries. Early lockdowns in SSA have been some of the strictest and resulted in devastating economic and social consequences and increased mortality from other health-related problems including maternal deaths. We review the literature and rationale supporting the various hypotheses that have been put forward to account for relatively low hospitalization and death rates for COVID-19 in SSA. We conclude that the strongest evidence would support the demographic age structure with a very low median age as the primary factor in leading to the low mortality seen in the first wave of the pandemic. The impact of new variants of concern in SSA raises the risk of more severe waves. Nevertheless, furthering the understanding of the underlying explanations for the low morbidity and mortality seen across SSA countries may allow the adoption of unique strategies for limiting the spread of COVID-19 without the need for stringent lockdowns…more