Confirmed new cases of Coronavirus disease 2019 (COVID-19) have accelerated in Sub-Saharan Africa against a backdrop of fragile health systems, a high burden of comorbidities and socioeconomic instability. The context makes the region particularly vulnerable to the virus and its impact. As cases escalate, the need to tailor-make COVID-19-related response strategies to the African context is imperative. This paper aims to discuss key considerations on the public health response to the pandemic and its intersection with ethics and human rights. With this perspective, we bring attention to the conflict between healthcare workers’ obligations and patient rights under the unclear policy and regulatory frameworks and the application of restrictive measures in the context of poverty. The indirect effects of the pandemic on already existing health problems are also highlighted. We appeal to the African States to establish appropriate systems which integrate human rights-based approaches to COVID-19 response. These systems should be ethically sound systems and ensure no-one is left behind in terms of testing, access to therapeutics and vaccination, and social protection; based on lessons learned over the past 12 months of the pandemic’s presence in SSA, and patterns emerging across the globe.