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The Esfahan Zayandeh-Roud River is the only water source for the Esfahan, Charmahal va Bakhtiari and Yazd provinces in Iran, and acts as a recipient for domestic, industrial and agricultural effluents. Parts of the river are already polluted. The population of the area is expected to grow rapidly, which will result in more pollutants entering the river as well as create greater demand on the river as a water source. Unless adequately managed, river quality may decrease to the point where it will not be able to meet the demands placed upon it. Qualitative and quantitative preservation of Zayandeh-Roud could help restore former conditions in the natural ecosystem. This can be achieved by pinpointing problem areas by SWAT model and using Best management practice (BMP) approaches. The main source of pollution in Zayandeh Roud River is agrochemical materials from agricultural drains, and in terms of organic pollutants, phosphorus and heavy metals from municipal and industrial sewages. Explorations related to Zayandeh Roud water quality have been very limited and mainly done by Esfahan regional water authority which are generally limited to pH and cation and anion concentration and were done in short periods. A comprehensive study on agricultural pollutants has never been accomplished in this watershed. There is not enough information about concentration of agricultural pollutants in the river. The main goal of this study was to test the suitability of the SWAT hydrologic model in simulating the hydrologic processes of the Zayandeh Roud watershed and then to assess effects of fertilizers on agricultural pollutants in Zayandeh Roud River. By using this scenario (Base Scenario) the hydrologic section of the model was calibrated. This was done by using flow data in four stations named: Ghale Shahrokh, Zayandeh Roud Dam, Pol-e-Kole and Varzaneh. The values simulated by the model were compared to measured values by using statistical indexes. The results were considered acceptable. On the basis of different values of fertilizers used in the region (urea and phosphorus fertilizers) five scenarios were defined. The first was almost close to the actual situation in the region. In the next step, effects of each fertilizer scenarios were assessed. These values were compared to the values related to base scenario and showed that the considerable effect of the amount of used fertilizers on the water quality of the river. The results of this study will assist to develop an effective management plan for the river to improve environmental conditions in Zayandeh-Roud watershed in Isfahan. At the end, some suggestions, based on the obtained results in order to reduce the effect of agricultural fertilizers are presented.