Issues of human rights abuse by multinational corporations (MNCs) in Africa are not unprecedented. From the colonial era to contemporary times, MNCs have been among Africa’s foremost violators of human rights. Their activities have had a significant negative impact on the human rights and environmental protection of African peoples. Importantly, these violations occur despite the explicit provisions for human rights protection in the African Charter on Human and People’s Rights, along with mechanisms such as the State Reporting Guidelines and Principles on Articles 21 and 24 of the African Charter Relating to Extractive Industries, Human Rights, and the Environment. In May 2023, the African Commission on Human and People’s Rights adopted Resolution 550 (LXXIV) on Business and Human Rights in Africa to address this anomaly. We hypothesize that this Resolution represents a significant achievement for human rights and environmental protection in the extractive sector in Africa. It offers valuable insight into the actual and much-anticipated regulation of the activities of transnational businesses, especially those operated by MNCs in Africa, through the African human rights systems. However, whether indeed the Resolution provides useful potential in advancing human rights and environmental protection by MNCs and other transnational business activities is a subjective issue that needs to be addressed. In this chapter, we critically examine Resolution 550 to highlight its prospects and constraints in holding MNCs accountable for human rights and environmental rights violations in Africa. We argue that Resolution 550 provides leverage and opportunities for advancing legal pathways to address environmental harm and human rights abuses by MNCs and other African businesses. Furthermore, it enables the adoption of a future African regional binding instrument that would help enhance human rights and environmental protection in the context of extractive industries and related business ventures in Africa.