Using protection motivation theory as the theoretical framework, this study investigates the factors that motivate COVID-19 response in Ghana, Cameroon, Lesotho and Uganda. Through simple random and snowball sampling techniques, 651 participants were selected. The study collected data with the aid of a survey questionnaire, which was analyzed through descriptive and inferential statistics. Results show high perceived COVID-19 threats among the respondents. Consequently, response strategies, such as wearing of nose mask, hand sanitizer application and social distancing, which are perceived to be effective, have been adopted. It is evident that respondents’ demographics influence their COVID-19 threats and coping strategies. Nevertheless, the severity of COVID-19 impacts ( p = .00), efficacy of response strategies ( p = .00) and access to COVID-19 information ( p = .02) were the significant predictors of COVID-19 response, even though the efficacy of COVID-19 response strategies (beta = .55) emerged as the best predictor. It is imperative for African governments to prioritize COVID-19 education to control the spread of the pandemic and minimize its impact.