Coronavirus disease 2019 (COVID-19) pandemic, caused by the Severe Acute Coronavirus 2 (SARS-CoV-2), is a global health threat with extensive misinformation and conspiracy theories. Therefore, this study investigated the knowledge, attitude and perception of sub-Saharan Africans (SSA) on COVID-19 during the exponential phase of the pandemic. In this cross-sectional survey, self-administered web-based questionnaires were distributed through several online platforms. A total of 1046 respondents from 35 SSA countries completed the survey. The median age was 33 years (18–76 years) and about half (50.5%) of them were males. More than 40% across all socio-demographic categories except participants from the Central African region (21.2%), those with vocational/secondary education (28.6%), as well as student/unemployed (35.5%), had high COVID-19 knowledge scores. Socio-demographic factors and access to information were associated with COVID-19 knowledge. Bivariate analysis revealed that independent variables, including the region of origin, age, gender, education and occupation, were significantly (p < 0.05) associated with COVID-19 knowledge. Multivariate analysis showed that residing in East (odds ratio [OR]: 7.9, 95% confidence interval (CI): 4.7–14, p < 0.001), Southern (OR: 3.7, 95% CI: 2.1–6.5, p < 0.001) and West (OR: 3.9, 95% CI: 2.9–5.2, p < 0.001) Africa was associated with high COVID-19 knowledge level. Apart from East Africa (54.7%), willingness for vaccine acceptance across the other SSA regions was < 40%. About 52%, across all socio-demographic categories, were undecided. Knowledge level, region of origin, age, gender, marital status and religion were significantly (p < 0.05) associated with COVID-19 vaccine acceptance. About 67.4% were worried about contracting SARS-CoV-2, while 65.9% indicated they would consult a health professional if exposed. More than one-third of the respondents reported that their governments had taken prompt measures to tackle the pandemic. Despite high COVID-19 knowledge in our study population, most participants were still undecided regarding vaccination, which is critical in eliminating the pandemic. Therefore, extensive, accurate, dynamic and timely education in this aspect is of ultimate priority.