A global sensitivity analysis was carried out on a water quality model to quantify the spatial changes in parameter sensitivity of a model of a large prairie river, the South Saskatchewan River (SSR). The method is used to assess the relative impacts of major nutrient loading sources and a reservoir on the river’s water quality. The river completely freezes over during winter; hence, the sensitivity analysis was carried out seasonally, for winter and summer, to account for the influence of ice-covered conditions on nutrient transformations. Furthermore, the integrity of the river’s aquatic ecosystem was examined through the inter-relationship between variables and comparing hierarchy index values and water quality indices at four locations along the river. Sensitivities of model parameters varied slightly at different locations along the river, with the phytoplankton growth rate being the most influential parameter. Nitrogen and phosphorus transformation processes were more sensitive in winter, while chlorophyll-a and dissolved oxygen parameters showed higher sensitivity in summer. A more complicated correlation between variables was observed downstream of the junction of the Red Deer River. Our results reveal that the lower correlation between variables may suggest a more balanced and healthier system, although further analysis is needed to support this statement.