The dumping of the raw municipal sewage in the Tigris River in Baghdad is also a major danger to the aquatic organisms, especially fish, which forms the source of food and livelihood of the local people. The current research examined the effects of sewage effluent on the African sharptooth catfish, i.e. Clarias gariepinus, by comparing the samples in reference (upstream) and sewage-afflicted (downstream) locations across a 15 kilometre stretch of the Tigris River near the Baghdad Medical City Complex. Water quality analysis revealed significantly elevated biochemical oxygen demand (BOD5 = 48–125 mg/L), chemical oxygen demand (COD = 85–215 mg/L), total suspended solids (TSS = 156–412 mg/L), and heavy metals (Pb: 0.35–0.78 mg/L; Cd: 0.12–0.31 mg/L; Zn: 1.2–3.8 mg/L) at impacted sites compared with reference sites (BOD5 = 4–8 mg/L; COD = 12–18 mg/L; TSS = 22–35 mg/L). The catfish in the sewage affected reaches showed a much lower condition factor (K = 0.85 ± 0.12 versus 1.24 ± 0.14, p < 0.001), high liver somatic index (LSI = 2.8 + 0.45 per cent versus 1.6 + 0.38 per cent, p < 0.001), and severe histopathological changes in the gills and liver, such as, epithelial hyperplasia, lamellar fusion, gill. Oxidative stress biomarkers indicated elevated lipid peroxidation (MDA: 18.5 ± 3.2 nmol/mg protein vs. 6.8 ± 1.5, p < 0.001) and depleted antioxidant defenses (reduced GSH: 15.3 ± 2.8 μmol/mg protein vs. 32.6 ± 4.1, p < 0.001) in livers of impacted fish. The indices of gill and liver lesions had positive significant correlations with biochemical oxygen demand (BOD; r = 0.78, p < 0.001) and heavy-metal concentrations (r = 0.72–0.81, p < 0.001). Those findings corroborate that continuous exposure to untreated sewage results in multisystemic pathology in catfish, and thus, affects the physiological fitness of catfish, and may lead to the loss of population viability. There should be urgent adoption of efficient wastewater treatment, strict effluent regulation as well as long-term monitoring of fish health in order to protect the Tigris River and human population relying on it.