Sediment and nutrient pollution in water bodies is threatening human health and the ecosystem, due to rapid land use changes and improper agricultural practices. The impact of the nonpoint source pollution needs to be evaluated for the sustainable use of water resources. An ideal tool like the soil and water assessment tool (SWAT) can assess the impact of pollutant loads on the drainage area, which could be beneficial for developing a water quality management model. This study aims to evaluate the SWAT model’s multi-objective and multivariable calibration, validation, and uncertainty analysis at three different sites of the Yarra River drainage area in Victoria, Australia. The drainage area is split into 51 subdrainage areas in the SWAT model. The model is calibrated and validated for streamflow from 1990 to 2008 and sediment and nutrients from 1998 to 2008. The results show that most of the monthly and annual calibration and validation for streamflow, nutrients, and sediment at the three selected sites are found with Nash–Sutcliffe efficiency values greater than 0.50. Furthermore, the uncertainty analysis of the model shows satisfactory results where the p-factor value is reliable by considering 95% prediction uncertainty and the d-factor value is close to zero. The model's results indicate that the model performs well in the river's watershed, which helps construct a water quality management model. Finally, the model application in the cost-effective management of water quality might reduce pollution in water bodies due to land use and agricultural activities, which would be beneficial to water management managers.