Evaluating how pollutant loads react to changes in land use/land cover (LULC) is a challenging task due to the intricate relationships among the many elements within a watershed. However, the difficulty in connecting LULC change and nonpoint source (NPS) pollution loads to streams may be lessened by combining hydrological modeling with geospatial tools and multivariate statistics. The objective of this study was to investigate the long-term effects of LULC change on NPS pollution loads in a highly human-dominated catchment, in central Ethiopia. In the study, hydrologic modeling was used to estimate the NPS parameters from multispectral Landsat images, and multivariate statistical techniques were then used to extract major LULC types that explain the variances of NPS loads between 1981 and 2020. The results demonstrated that there were human-induced LULC changes in the area, as the built-up and agricultural landscapes are rising (186.4% and 5.8%, respectively), and shrub and forest lands are decreasing (67.1% and 41%, respectively). As a result of these changes, the concentrations of nitrate (NO3), total P, total N, organic N, and organic P loads were increased by 69.41, 19.83, 18.45, 18.88, and 24.05%, respectively. Reductions in natural vegetation, as well as agriculture intensification, are the major contributors to the NPS pollutant losses to surface water sources. The result also revealed that pollution nutrients are strongly related to deforestation and agricultural land expansion. Proper adaptation strategies should be implemented to minimize the negative impact of LULC changes in the area.