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Background: The coronavirus disease (COVID-19) outbreak has caused a universal health crisis resulting in significant morbidities and mortalities particularly among high-risk groups. This study sought to determine regional factors associated with knowledge and attitude towards COVID-19 mitigation practices and risk perception of contracting the disease in Sub-Saharan African (SSA) countries. Methods: A cross-sectional anonymous online study was conducted among 1970 participants between April and May 2020, during the lockdown in many SSA countries. Recruitment of participants was via WhatsApp, Facebook and emails using authors' networks. The outcome variables were KAP (knowledge, attitudes and practice) of COVID-19 and analysis of variance (ANOVA) with post hoc test was run to assess the level of KAP by four regions in SSA. Simple and multiple linear regression (MLR) analyses were performed to examine factors associated with the outcome measures in the four SSA regions. Results: Mean knowledge (P = 0.707) and risk perception (P = 0.904) scores by four regions in SSA did not differ significantly. However, the mean attitude score was higher among West Africans compared with Southern (P = 0.019) and Central Africans (P = 0.003). MLR analysis revealed that among those living in West (adjusted coefficient β = -0.83 95% CI: -1.19, -0.48) and Southern Africa (β = -0.91 95% CI: -1.42, -0.40), having a primary or secondary education was associated with a decrease in knowledge scores while not being worried about COVID-19 decreased risk perception scores across the four SSA regions(West [β = -6.57, 95% CI: -7.53, -5.62], East [β = -6.24: 95% CI: -8.34,-4.15], Central [β = -6.51, 95% CI: -8.70, -4.31], and Southern Africa [β = -6.06: 95% CI: -7.51, -4.60]). Except among Southern Africans, participants who practiced self-isolation had positive attitude towards COVID-19. Conclusion: Future research on health education regarding COVID-19 or a future related pandemic in SSA should target people with lower education, those who do not self-isolate, those living in Southern and Western Africa and not worried about contracting COVID-19. [ABSTRACT FROM AUTHOR]