The Eastern Nile riparian countries are currently developing several reservoir projects to contribute to the needs for energy and food production in the region. In the absence of formal mechanisms for collaboration, the transboundary nature of the Eastern Nile basin makes water resources development challenging. The large seasonal and interannual variability of the river flow increases those challenges. This paper assesses the implications of water resources development in the Eastern Nile basin on water availability for hydropower generation and irrigation demands at country and regional levels, using simulation and scenario analysis methods. Twelve scenarios are used to test developments of several dams and irrigation demands, Grand Ethiopian Renaissance Dam (GERD) operation options, and unilateral (status quo) versus integrated transboundary management of dams. A RIBASIM model that included 20 dams and 21 irrigation schemes was built, using a complete data set of 103 years at a monthly time step. Four indicators have been used for evaluating the performance of the system: hydroenergy generation (MWh=year), reliability of irrigation supply (%), reservoir net evaporation (10⁶ m³/year), and flow regimes of rivers (m³/s). The results show that in case of managing the system in an integrated transboundary manner and without new irrigation development projects, GERD would increase the hydroenergy generation in Ethiopia by + 1,500% and in Sudan by + 17%, with a slight reduction in Egypt of -1%. Supply reliability of existing and planned irrigation schemes in Sudan would not be practically influenced by the GERD, but the reliability will be reduced by about 8% when upstream development and new irrigation expansion materialize. Full development of the Eastern Nile basin would reduce the irrigation supply reliability in Egypt to 92% compared to the base scenario (100%). Compared to integrated management, unilateral management would increase the hydroenergy generation in Ethiopia (+16%), increase the rate of evaporation losses in the basin (+15%), and reduce the irrigation supply reliability in Sudan after full development of dams and irrigation projects (-10%). Water resources development would have considerable but varying effects on the countries.