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This paper examines the determinants of the spread of coronavirus disease 2019 (COVID-19) in Africa, based on the framework of social determinants of health. Applying Poisson Pseudo Maximum Likelihood (PPML) and quantile regressions to panel data and country-specific socioeconomic background data from 53 African countries, the study finds that enhancing capacity for early testing helps for timeous uncovering of cases, early isolation and contact tracing for effective control of the spread. Other factors such as managing of international movements through reduction of international exposure and ensuring better sanitation and hygiene were found to be relevant in diminishing COVID-19 spread, whereas alcohol consumption and population density heighten the spread. The work also highlights that stringent measures will be counter-productive unless they are coupled with measures to create and preserve livelihoods, together with humanitarian relief assistance to the poorest segments of the population. The results are robust to alternative techniques. As policy recommendations, we implore African governments to the promotion of sustainable livelihoods and social safety nets as measures to accompany stringent lockdowns; and good sanitation programmes to become a lifestyle of citizens. Careful attention should be paid to the socioeconomic trade-off in respect of international travel restrictions given the high dependence of most African economies on tourism., (© 2021 African Development Bank.)