The differential spread and impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing Coronavirus Disease 2019 (COVID-19), across regions is a major focus for researchers and policy makers. Africa has attracted tremendous attention, due to predictions of catastrophic impacts that have not yet materialized. Early in the pandemic, the seemingly low African case count was largely attributed to low testing and case reporting. However, there is reason to consider that many African countries attenuated the spread and impacts early on. Factors explaining low spread include early government community-wide actions, population distribution, social contacts, and ecology of human habitation. While recent data from seroprevalence studies posit more extensive circulation of the virus, continuing low COVID-19 burden may be explained by the demographic pyramid, prevalence of pre-existing conditions, trained immunity, genetics, and broader sociocultural dynamics. Though all these prongs contribute to the observed profile of COVID-19 in Africa, some provide stronger evidence than others. This review is important to expand what is known about the differential impacts of pandemics, enhancing scientific understanding and gearing appropriate public health responses. Furthermore, it highlights potential lessons to draw from Africa for global health on assumptions regarding deadly viral pandemics, given its long experience with infectious diseases.