Water is critical for leveraging development opportunities in East Africa. Identifying sustainable water-development pathways in the context of climate change and environmental protection is imperative for water security. We co-developed regional water scenarios together with local stakeholders. A hydro-economic assessment of the headwaters of the Nile River revealed interconnections among socio-economic development, climate change, and the environment. In an increasing number of months and sub-basins, advanced water-saving technologies and management are needed to avoid local water-scarcity hotspots.