This study employed an integrated field monitoring approach, combining chemical analysis and ecotoxicity testing of multiple environmental matrices—water, sediment, and sediment elutriates—to comprehensively assess the environmental health of the Andong watershed, located near a Zn smelter and mining area. The primary objectives were to evaluate the extent of metal contamination, identify key toxicants contributing to ecological degradation, and trace the sources of these pollutants. Our findings revealed severe metal contamination and significant ecotoxicological effects both in proximity to and downstream from industrial sites. Specifically, Cd, Zn, and Pb were strongly linked to the smelter, while Hg, Ni, Cu, and As were predominantly associated with mining activities in the tributaries. To further assess toxicity of field-collected sediment and their elutriates, a logistic regression analysis was employed to estimate benchmark values for distinguishing between toxic and non-toxic samples, using the sum of toxic units for sediment elutriates and the mean probable effect level (PEL) quotient for sediment toxicity. These models demonstrated greater predictive accuracy than conventional benchmarks for determining toxicity thresholds. Our results highlight that integrating chemical and ecotoxicological monitoring with site-specific concentration–response relationships enhances the precision of ecological risk assessments, facilitating more accurate identification of key toxicants driving mixture toxicity in complex, pollution-impacted aquatic ecosystems.