Background: During its first wave of COVID-19 infection in sub-Saharan Africa, there was insufficient understanding of the pandemic among frontline health workers. This study was carried out to determine the knowledge, attitude, and practices (KAP) of frontline health workers (HWs) towards COVID-19 in Africa and their related factors. Methods: This was a multicenter online cross-sectional study conducted between April 2020 and July 2020 using a Google survey link among frontline HWs involved in the COVID-19 response in 26 African countries. Bivariate and multivariate logistic regression were used to analyse the determinants of KAP. Data were analyzed using STATA ver 16; all tests were two-sided with 95% confidence interval.