The study was to characterize and understand the water quality of the river Yamuna in Delhi (India) prior to an efficient restoration plan. A combination of collection of monitored data, mathematical modeling, sensitivity, and uncertainty analysis has been done using the QUAL2Kw, a river quality model. The model was applied to simulate DO, BOD, total coliform, and total nitrogen at four monitoring stations, namely Palla, Old Delhi Railway Bridge, Nizamuddin, and Okhla for 10 years (October 1999–June 2009) excluding the monsoon seasons (July–September).