The coronavirus disease (COVID-19) has spread quickly across the globe with devastating effects on the global economy as well as the regional and societies' socio-economic fabrics and the way of life for vast populations. The nonhomogeneous continent faces local contextual complexities that require locally relevant and culturally appropriate COVID-19 interventions. This paper examines demographic, economic, political, health, and socio-cultural differentials in COVID-19 morbidity and mortality. The health systems need to be strengthened through extending the health workforce by mobilizing and engaging the diaspora, and implementing the International Health Regulations (2005) core capacities. In the absence of adequate social protection and welfare programs targeting the poor during the pandemic, sub-Saharan African countries need to put in place flexible but effective policies and legislation approaches that harness and formalise the informal trade and remove supply chain barriers. This could include strengthening cross-border trade facilities such as adequate pro-poor, gender-sensitive, and streamlined cross-border customs, tax regimes, and information flow. The emphasis should be on cross-border infrastructure that not only facilitates trade through efficient border administration but can also effectively manage cross-border health threats. There is an urgent need to strengthen social protection systems to make them responsive to crises, and embed them within human rights-based approaches to better support vulnerable populations and enact health and social security benefits. The COVI-19 response needs to adhere to the well-established 'do no harm' principle to prevent further damage or suffering as a result of the pandemic and examined through local lenses to inform peace-building initiatives that may yield long-term gains in the post-COVID-19 recovery efforts.