Africa must overcome persistent global health inequities by establishing itself as a sovereign health actor and global leader. This chapter examines Africa’s trajectory towards self-reliance in health systems and governance, highlighting the Africa CDC (Africa Centres for Disease Control and Prevention) and the African Medicines Agency (AMA) as transformative institutions promoting regulatory harmonization and policy innovation. Using the Africa CDC’s COVID-19 response and initiatives to reduce pharmaceutical import dependency as case studies, it demonstrates the continent’s progress towards health self-determination. The chapter explores how multi-sectoral partnerships, exemplified by the “Zero Malaria Starts with Me” campaign, advance African-led healthcare solutions. It emphasizes increased domestic health expenditure as crucial for reducing donor dependency and positions health sovereignty as a catalyst for equitable healthcare, economic growth, and Africa’s emergence as a global health authority.