The human population of the Nile basin has been vulnerable to water-associated diseases since the dawn of history. In the modern landscape, water development projects and expanded irrigation are considered vital for increasing agricultural productivity and improving the socioeconomic status of rural communities. However, these projects also have the potential to modify hydrological processes in a way that increases the risk of water-associated diseases. To explore these interactions, we first outlined the major hydrological determinants of three important water-associated diseases within the Nile basin: cholera, a water-borne disease; schistosomiasis, a water-based disease; and malaria, a water-related disease. We then reviewed the scientific literature that has examined the influences of dams, irrigation schemes, and other water-management practices on these diseases within the Nile basin. Our synthesis of the literature emphasizes the importance of integrating public health concerns into the planning of new water development projects in the Nile basin and also highlights the potential for utilizing the underlying hydro-epidemiological relationships to enhance mapping and forecasting of water-associated disease risk under current and future climates.