Introduction <p>Emerging and re-emerging public health threats, predominantly zoonotic in nature, pose significant challenges to health systems globally. This review aims to determine the drivers, challenges, and opportunities of the One Health Approach in Africa, where the current state of affairs may differ even from that of other low- and middle-income nations.</p> Methods <p>This systematic review followed the PRISMA 2020 guidelines. A comprehensive literature search was conducted across Google Scholar, PubMed, and Scopus, focusing on studies published between 2010 and April 2024. The review included 13 studies from various African countries, selected based on predefined inclusion criteria. Qualitative, Content analysis was conducted to identify key drivers, challenges, and opportunities influencing OHA implementation.</p> Results <p>Key drivers for One Health Approach adoption included strong political commitment, existing multisectoral collaboration, and international donor support. Recurrent zoonotic outbreaks and environmental changes further motivated integration efforts. However, challenges such as fragmented governance, limited financial resources, workforce capacity deficits, and weak surveillance systems hinder widespread adoption. Despite these barriers, opportunities exist to strengthen policy frameworks, leverage digital health tools, expand community engagement, and foster international partnerships.</p> Conclusion <p>The findings underscore the critical need for sustained political will, enhanced resource allocation, and continuous capacity building to optimize OHA outcomes in Africa. By addressing systemic limitations, integrating One Health into policies, establishing sustainable finances, and harnessing available opportunities such as training, African nations can build resilient health systems capable of proactively managing public health threats, ultimately advancing regional and global health security.</p>