In this study, adverse impacts of heavy metal pollution, originating from mining, smelting and panning activities, on the aquatic ecosystem of the Lean River in south China, were evaluated by integrating the chemical, toxicological and ecological responses of single and multiple metals in overlying water, surface sediment and floodplain topsoil. The assessment results indicated that a highly localized distribution pattern was closely associated with the pollution sources along the river bank. Based on the combined indices, deterioration of local environmental quality was induced mainly by two sources. One was strong acidity and a large amount of Cu in the drainage from the Dexing Cu Mine. Another was high concentrations of Pb and Zn in the effluents released from many smelters and mining/panning activities in the riparian zone. Some possible suggestions on source control may be effective in dealing with these issues.