Despite representing 18% of the world’s population and 20% of the disease burden, only an estimated 2% of global clinical trials include at least one study site in Africa. This underscores the critical need for continued research on how to overcome clinical trial challenges on the continent. In countries with established reputations for clinical trials, Contract Research Organizations (CROs) play a vital role, accounting for half of the research workforce and effectively managing clinical trials for pharmaceutical, biotechnology, and medical device companies. In contrast, the potential of CROs in Africa’s clinical trials ecosystem remains largely unexplored. This narrative review discusses the challenges, opportunities, best practices, emerging trends, and prospects of clinical trials in Africa. Major challenges in clinical trial implementation in Africa stem from gaps in financial and human resources, infrastructure, and regulatory systems, while opportunities are linked to Africa’s large population, genetic diversity, disease burden, lower operating costs, positive economic outlook, and growing interest from global health and research players. Emerging trends, such as the decentralization of clinical trials and conducting trials during public health emergencies, offer promising avenues for maintaining research continuity. Ultimately, the paper proposes a context-specific framework, aimed at maximizing the effectiveness of CROs in the continent’s clinical trials ecosystem.