The concept of One Health and its application remain very important to addressing the existential challenges facing the African continent and the entire globe considering human-animal-environmental health risks and their impacts. The massive human and animal (especially livestock and those in the wild) populations have showcased Africa as a force to reckon with when conceptualising One Health, considering the exceptional features and peculiarities of the region. The African environment is endowed with a huge diversity of wildlife existing in large land mass, that interacts in various ways with humans, presenting the challenge of a high burden of infectious diseases. In addition, human existence is dependent on food, water, and other resources as primary needs. Availability of food and clean municipal water promote public health and sustained development.   Humans, animals, and plants all depend on water and food for survival. Therefore, the One Health Concept in the African context must consider these unique features, in addition to existential challenges of insecurity, poor governance and breakdown of health systems that infringe on human right to quality healthcare, especially in resource-poor countries on the continent, late detection of infectious diseases that deter rapid response to and management of epidemics. In this chapter, One Health concept in Africa is based mostly on the standard interplay between human-animal-environment, interplay with a particular emphasis on human interactions with the environment that contribute to sustained burden of diseases, especially transmission of diseases through water and food in the continent.