A simulation-based optimization framework for agricultural drainage water (ADW) reuse has been developed through the integration of a water quality model (QUAL2Kw) and a genetic algorithm. This framework was applied to the Gharbia drain in the Nile Delta, Egypt, in summer and winter 2012. First, the water quantity and quality of the drain was simulated using the QUAL2Kw model. Second, uncertainty analysis and sensitivity analysis based on Monte Carlo simulation were performed to assess QUAL2Kw's performance and to identify the most critical variables for determination of water quality, respectively. Finally, a genetic algorithm was applied to maximize the total reuse quantity from seven reuse locations with the condition not to violate the standards for using mixed water in irrigation. The water quality simulations showed that organic matter concentrations are critical management variables in the Gharbia drain. The uncertainty analysis showed the reliability of QUAL2Kw to simulate water quality and quantity along the drain. Furthermore, the sensitivity analysis showed that the 5-day biochemical oxygen demand, chemical oxygen demand, total dissolved solids, total nitrogen and total phosphorous are highly sensitive to point source flow and quality. Additionally, the optimization results revealed that the reuse quantities of ADW can reach 36.3% and 40.4% of the available ADW in the drain during summer and winter, respectively. These quantities meet 30.8% and 29.1% of the drainage basin requirements for fresh irrigation water in the respective seasons.