Metal and nutrient pollution, soil erosion, and alterations in climate and hydrology are prevalent issues that impact the water quality of riverine systems. However, integrated approaches to assess and isolate causes and paths of river water pollution are scarce, especially in the case of watersheds impacted by multiple hazardous activities. Therefore, a framework model for investigating the multiple sources of river water pollution was developed. The chosen study area was the Paraopeba River basin located in the Minas Gerais, Brazil. Besides multiple agriculture, industrial, and urban pollution sources, this region was profoundly affected by the rupture of the B1 tailings dam (in January 2019) at the Córrego do Feijão mine, resulting in the release of metal-rich waste. Considering this situation, thirty-nine physicochemical and hydromorphological parameters were examined in the Paraopeba River basin, in the 2019–2023 period. The analysis involved various statistical techniques, including bivariate and multivariate methods such as correlation analysis, principal component analysis, and clustering. The Paraopeba River was mainly impacted by metal contamination resulting from the dam collapse, whereas nutrient contamination, mainly from urban and industrial discharges, predominantly affected its tributaries. Additionally, the elevated concentrations of aluminum, iron, nitrate, and sulfate in both main river and tributaries can be attributed to diffuse and point source pollution. In terms of hydromorphology and soil type, the interaction between woody vegetation and erosion-resistant soils, especially latosols, contributes to the stability of riverbanks in the main river. Meanwhile, in the tributaries, the presence of neosols and sparse vegetation in urbanized areas promoted riverbank erosion potentially amplifying pollution. While the study was conducted in a particular watershed, the findings are based on a methodology that can be applied universally. Hence, the insights on surface water quality from this research can be a valuable resource for researchers studying watersheds with diverse pollution sources.