The Karkheh Dam Reservoir with a capacity of more than 5 billion cubic meter is the largest dam in Iran with both agricultural and drinking usages. Its hydrodynamics and water quality were modeled and simulated to analyze the total maximum daily load (TMDL) of Total Dissolved Solids (TDS). The simulation was supported with measurements of temperature and TDS measurements during two years. A laterally averaged 2D model called CE-QUAL-W2 was used for the simulation and hypothetical low height spillways were implemented in the model to avoid drying of the cells in the river branch. The model was then calibrated successfully with an absolute mean error of 0.71* C. More importantly, vertical stratification of temperature and TDS in the Karkheh Reservoir was reproduced by the model throughout years 2000 to 2003. The calibrated model was then used to simulate water quality response to various TDS reduction scenarios. Model results reveal that a 50% reduction of the TDS load is required for a 40% reduction of TDS in the reservoir outlet. The modeling of a complex combination of a steep and long river -reservoir system was another important achievement of this study.