<p>The methodology developed in this study includes an expanded conceptual model and the application of the Water Evaluation and Planning (WEAP) model for hydrological modeling of a transboundary river basin. This methodology was applied to the Tigris-Euphrates Transboundary River (TETR) basin to assess the impact of unilateral development projects on downstream water resources. A 41-year modeling period (1979–2019) was used, including planned development engineering projects in the region. The model was calibrated and validated using flow measurements of 22 stations where their records’ length varied between 1979 and 2015. The range of statistical criteria of NSE and PBIAS was also between 0.1 to 0.82 and 8.0 to 48.8 for calibration and 0.01 to 0.99 and 6.6 to 62.4 for validation periods, respectively. Except 6 stations, the rest were in the acceptable ranges. Scenarios for the unilateral development projects were defined and the sustainability of water supply and demand was assessed using the established indicators. Sustainability Index at country level (SCL) indicated that the development projects in Turkey contributed more to the sustainability of the country’s water resources. However, their control of the downstream flow of both the Tigris and Euphrates rivers led to a 59% decrease in the SCL for Syria, a 60% decrease for Iraq, and a 32% increase for Turkey. The simulation results for Hammar Lake showed a significant negative trend in inflow, with the average flow at 209 m³/s from 1979 to 2019. These results demonstrated that increasing upstream activities and decreasing inflow from main tributaries will have profound social, economic, and environmental impacts on downstream regions. The risk analysis under uncertainty also indicated a higher risk of sustainability decrease for Iraq and Syria compared to Turkey. The results of Sustainability Index and risk analysis from this study could be helpful for decision-makers in the water management to develop effective, sustainable water resource strategies.</p>