Under pressure from existing and emerging contaminants, lotic ecosystems are becoming increasingly susceptible to ecological deterioration. Therefore, investigations of the impacts of persistent organic pollutants (POPs) and heavy metals on riverine fish health, water quality, and biotic integrity are critical. We examined the effects of 52 POPs and heavy metals on ecological health and land use, based on the monitoring of fish assemblages and river water quality from 2007 to 2014. Among the 52 chemical species, 35 were present in water and fish tissues, including eight heavy metals. The concentrations of these POPs and heavy metals in 12 fish species are presented. Most POPs were either undetected or present at negligible levels in fish tissues, although a few polycyclic aromatic hydrocarbons (PAHs) and organochlorine pesticides (OCPs; dichlorodiphenyltrichloroethanes and heptachlor epoxide) were detected above the screening values (SVs). Hg, As, and Cd were detected in most water samples and fish species at concentrations above their SVs. Among the fish species in the investigated trophic guild, heavy metal contents were in the order of Zn < Cr < Cu < Pb < Se, while trophic levels were in the order of insectivorous < omnivorous < carnivorous. Agricultural cover showed an association with endosulfan II (R2 = 0.50, r = 0.70), followed by alachlor (R2 = 0.43, r = 0.66). For PAHs, all detected substances showed significant relationships with forest cover. Ecological health assessment revealed that most river sites are in poor condition, indicating the direct impacts of pollutants. In conclusion, of the 28 POPs detected, 16 PAHs and 3 OCPs (hexachlorobenzene, lindane, and heptachlor epoxide) were of significant concern, such that action is needed to curb their inflow to the riverine environment. The studied river basin is under substantial threat from harmful POPs that endanger ecological health and fish biodiversity.