Dog-mediated human rabies is a severe and dreadful viral disease. It is not only endemic in many African countries but also causes mortality and economic losses in the affected countries. The One Health approach has effectively demonstrated the constructive evidence to control and prevent this disease in many African countries. In this chapter, a systematic review was conducted to screen all the peer-reviewed publications through Google Scholar, Medline, Scopus, Web of Science, Science Direct, and rabies web conferences that have demonstrated the benefits and various field challenges in controlling dog-mediated human rabies using the One Health approach in the African subcontinent. This chapter will highlight categorical issues and challenges in adopting the One Health approach at the municipal, city, provincial, and national levels. Various technical, administrative, socio-anthropological, and scientific barriers have been observed and interpreted in detail.