While there is increasing reference in extant literature to Nigeria and South Africa’s domestic responses to the COVID-19 pandemic, there is limited analysis on the states’ responses in both the domestic and international contexts as regional powers in Africa. This chapter seeks to fill this gap by exploring Nigeria and South Africa’s initial responses domestically and the regional powers’ roles in the Economic Community of West African States (ECOWAS), Southern African Development Community (SADC), African Union (AU), and their engagements with external actors such as the International Monetary Fund (IMF), World Bank, and European Union (EU) towards combatting the pandemic. It submits that Abuja and Pretoria leveraged their status as regional powers to provide leadership in African multilateral institutions, especially ECOWAS, SADC, and the AU, and to engage external powers towards ameliorating the socioeconomic impact of the pandemic in their respective countries and Africa, more broadly.