Blood and blood products save lives and are a part of the WHO Essential Medicines List. Access to safe and quality-assured blood and blood products are essential for health systems strengthening and it is a global concern. Their use is associated with infectious and immunologic risks. At global level, many resolutions have been adopted by the World Health Assembly that urged Member States to ensure regulatory control of access to quality-assured blood and blood products along the entire transfusion chain. The WHO has also developed an action framework to advance universal access to blood. As part of the implementation of these resolutions and guidelines, the WHO Regional Office for Africa and some partners provided support to countries in the region to strengthen their capacity to establish an effective blood regulatory system through organization of regional training workshops on blood regulation, benchmarking of blood regulatory systems, internship at Paul Ehrlich Institut and establishment of the African Blood Regulators Forum. The current status of blood regulation reveals that there are weak transfusion legislation and blood regulatory systems in most African countries, since many national blood transfusion services still rely on self-regulation. However, the national regulatory authorities have reached the maturity level 3 in two countries (Ghana and Tanzania), but only the experience from Ghana has been described in this paper. Like in other low- and middle-income countries, the regulatory systems for associated substances and medical devices including IVDs are not well established in the African region. Misunderstanding by different stakeholders, lack of legislation that provides legal basis, weak capacity and insufficiency of resources are main challenges facing countries to establish an effective national blood regulatory system. To address these challenges, strong advocacy with governments and collaboration with partners are needed to strengthen national blood regulatory systems.