This study was initiated to evaluate the effect of hazardous exposure to water pollutants on Tilapia zilli Gerv, inhabiting Lake Maryût, at 3 different sites with varying degrees of physicochemical and organic criteria. As compared to other sites, the lower water turbidity and alkalinity plus lesser metal content in site #1, signify its picking as reference.The expected anoxicity of the polluted sites (#2& #3) was evidenced by the elevated chemical‐and biological‐oxygen demands added to reduced dissolved oxygen. Abundant phytoplankton and sewage effluents coupled with the high productivity of the lake have elevated water pH and nutrient salts; thus causing a chronic eutrophication problem. Emerging evidence suggests that T. zilli, responded differently according to the environmental stress index in each catch area. In polluted fish, serum hyper‐αl‐, α₂‐, and β‐globulinemia plus low albumin added to the enhanced activities of serum transaminases and lactate dehydrogenase suggests chronic functional damage in the liver. However, the hyper‐y‐globulinemia implies an indirect challenge response toward the invasion of endo‐and ectoparasites. Serum enzymes, protein, lipid, cholesterol, creatinine, and glucose fluctuated in a positive correlation contra the guidelines of water pollutants; they are thus validated as beneficial "biochemical markers”;, for contamination stress. Unlike other biological principles investigated, alkaline phosphatase proved to be a promising "model”;, for appraising moderate, sublethal, or metal‐ restricted contamination,. Other water pollutants, as petroleum oil, seem to interfere with this peculiarity.