This study describes risk factors associated with mortality among COVID-19 cases reported in the WHO African region between 21 March and 31 October 2020. Average hazard ratios of death were calculated using weighted Cox regression as well as median time to death for key risk factors. We included 46 870 confirmed cases reported by eight Member States in the region. The overall incidence was 20.06 per 100 000, with a total of 803 deaths and a total observation time of 3 959 874 person-days. Male sex (aHR 1.54 (95% CI 1.31–1.81); P < 0.001), older age (aHR 1.08 (95% CI 1.07–1.08); P < 0.001), persons who lived in a capital city (aHR 1.42 (95% CI 1.22–1.65); P < 0.001) and those with one or more comorbidity (aHR 36.37 (95% CI 20.26–65.27); P < 0.001) had a higher hazard of death. Being a healthcare worker reduced the average hazard of death by 40% (aHR 0.59 (95% CI 0.37–0.93); P = 0.024). Time to death was significantly less for persons ≥60 years (P = 0.038) and persons residing in capital cities (P < 0.001). The African region has COVID-19-related mortality similar to that of other regions, and is likely underestimated. Similar risk factors contribute to COVID-19-associated mortality as identified in other regions.