Lack of interoperability and integration between heterogeneous health systems is a big challenge to realize the potential benefits of eHealth. To best move from siloed applications to interoperable eHealth solutions, health information exchange (HIE) policy and standards are necessary to be established. However, there is no comprehensive evidence on the current status of HIE policy and standards on the African continent. Therefore, this paper aimed to systematically review the status of HIE policy and standards which are currently in practice in Africa. A systematic search of the literature was conducted from Medical Literature Analysis and Retrieval System Online (MEDLINE), Scopus, Web of Science, and Excerpta Medica Database (EMBASE), and a total of 32 papers (21 strategic documents and 11 peer-reviewed papers) were selected based on predefined criteria for synthesis. Results revealed that African countries have paid attention to the development, improvement, adoption, and implementation of HIE architecture for interoperability and standards. Synthetic and semantic interoperability standards were identified for the implementation of HIE in Africa. Based on this comprehensive review, we recommend that comprehensive interoperable technical standards should be set at each national level and should be guided by appropriate governance and legal frameworks, data ownership and use agreements, and health data privacy and security guidelines. On top of the policy issues, there is a need to identify a set of standards (health system standards, communication, messaging standards, terminology/vocabulary standards, patient profile standards, privacy and security, and risk assessment) and implement them throughout all levels of the health system. On top of this, we recommend that the Africa Union (AU) and regional bodies provide the necessary human resource and high-level technical support to African countries to implement HIE policy and standards. To realize the full potential of eHealth in the continent, it is recommended that African countries need to have a common HIE policy, interoperable technical standards, and health data privacy and security guidelines. Currently, there is an ongoing effort by the Africa Centres for Disease Control and Prevention (Africa CDC) towards promoting HIE on the continent. A task force has been established from Africa CDC, Health Information Service Provider (HISP) partners, and African and global HIE subject matter experts to provide expertise and guidance in the development of AU policy and standards for HIE. Although the work is still ongoing, the African Union shall continue to support the implementation of HIE policy and standards in the continent. The authors of this review are currently working under the umbrella of the African Union to develop the HIE policy and standard to be endorsed by the head of states of the Africa Union. As a follow-up publication to this, the result will be published in mid-2022.