Ndarugu River, Kenya, during its course through the different agricultural and industrial areas of Gatundu, Gachororo and Juja farms, receives untreated industrial, domestic and agricultural waste of point source discharges from coffee and tea factories. During wet season the water is also polluted by non-point (diffuse) sources created by runoff carrying soil, fertilizer and pesticide residues from the catchment area. This study involved the calibration of water quality model QUAL2K to predict the water quality of this segment of the river. The model was calibrated and validated for flow discharge (Q), temperature (T˚), flow velocity (V), biochemical oxygen demand (BOD5), dissolved oxygen (DO) and nitrate (NO3-N), using data collected and analyzed during field and laboratory measurements done in July and November-December 2013. The model was then used in simulation and its performance was evaluated using statistical criteria based on correlation coefficient (R2) and standard errors (SE) between the observed and simulated data. The model reflected the field data quite well with minor exceptions. In spite of these minor differences between the measured and simulated data set at some points, the calibration and validation results are acceptable especially for developing countries where the financial resources for frequent monitoring works and higher accuracy data analysis are very limited. The water is being polluted by the human activities in the catchment. There is need for proper control of wastewater by various techniques, and preliminary treatment of waste discharges prior to effluent disposal. Management of the watershed is necessary so as to protect the river from the adverse impacts of agricultural activities and save it from further deterioration.