This study examined the effect of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) on labour productivity in Africa and its sub-regions while controlling for the moderating effect of literacy rate. The study used the system Generalised Method of Moment estimation technique and annual panel data from 2010 to 2020 for 53 African economies. Labour productivity and literacy rate were measured by the ratio of gross domestic product to total employment and gross secondary school enrolment respectively. The results indicate that HIV/AIDS retards labour productivity, and that literacy rate can ease this depressing effect of HIV/AIDS in Africa. The sub-regional differences in Africa obtained in this study revealed that the depressing effect of HIV/AIDS on labour productivity is highest in Southern Africa and lowest in Northern and Central Africa. Interestingly, the study also established that per capita health expenditure, per capita income, gross capital formation, and information and communications technology are important drivers of labour productivity in Africa. The study, therefore, concludes that there is need for governments and other stakeholders to help to increase school enrolment and improve the quality of the content of education curriculum in Africa to increase the awareness of HIV/AIDS, especially as it relates to its channels of transmission like unprofessional blood transfusion, unprotected sexual activity, and genital mutilation, among others.