Background With COVID-19 being a newly evolving disease, its response measures largely depend on the practice of and compliance with personal protective measures (PPMs). Objective This systematic review aimed to examine the knowledge and practice of COVID-19 PPMs in African countries as documented in the published literature. Methods A systematic search was conducted on the Scopus, PubMed, and Web of Science databases using appropriate keywords and predefined eligibility criteria for the selection of relevant studies. Only population-based original research studies (including qualitative, quantitative, and mixed methods studies) conducted in Africa and published in the English language were included. The screening process and data extraction were performed according to a preregistered protocol in PROSPERO (CRD42022355101) and followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The quality of the included studies was assessed using the Mixed Methods Appraisal Tool. Thematic analysis was used to systematically summarize the studies into 4 predefined domains: knowledge and perception of PPMs, mask use, social and physical distancing, and handwashing and hand hygiene, including their respective levels and associated factors. Results A total of 58 studies across 12 African countries were included, published between 2019 and 2022. African communities, including various population groups, had varying levels of knowledge and practice of COVID-19 PPMs, with the lack of personal protective equipment (mainly face masks) and side effects (among health care workers) being the major reasons for poor compliance. Lower rates of handwashing and hand hygiene were particularly noted in several African countries, especially among low-income urban and slum dwellers, with the main barrier being the lack of safe and clean water. Various cognitive (knowledge and perception), sociodemographic, and economic factors were associated with the practice of COVID-19 PPMs. Moreover, there were evident research inequalities at the regional level, with East Africa contributing 36% (21/58) of the studies, West Africa contributing 21% (12/58), North Africa contributing 17% (10/58), Southern Africa contributing 7% (4/58), and no single-country study from Central Africa. Nonetheless, the overall quality of the included studies was generally good as they satisfied most of the quality assessment criteria. Conclusions There is a need to enhance local capacity to produce and supply personal protective equipment. Consideration of various cognitive, demographic, and socioeconomic differences, with extra focus on the most vulnerable, is crucial for inclusive and more effective strategies against the pandemic. Moreover, more focus and involvement in community behavioral research are needed to fully understand and address the dynamics of the current pandemic in Africa. Trial Registration PROSPERO International Prospective Register of Systematic Reviews CRD42022355101; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022355101