Key words:Biochemical; Histopathology; Oreochromis niloticus; Lake EdkuThe main objective of this study is to assess some biochemical and histopathological changes in Nile Tilapia, Oreochromis niloticus caught from Lake Edku. A decrease in serum total protein, albumin, total lipids, bactericidal activity, ALT and AST was observed in El-Maadyah and Edku drain regions compared to recovery group, while the levels of serum glucose and lysozyme activity were increased. The frequencies of micronucleus (MN) and nuclear abnormalities (NAs) in fish erythrocytes showed an increase of micronuclei, lobed nuclei and fragmented apoptotic nuclei while notched nuclei were decreased. Finally, the frequencies of morphologically altered erythrocytes (MAEs) of fish showed an increase in swelled cells, vacuolated cytoplasm; microcytes; echinocytes; teardrop like; sickle cells and nuclear retraction. On the other hand, the main prominent hepatic lesions were parasitic granuloma, encapsulated parasitic cysts by connective tissue, fatty degeneration, congestion and necrosis. The histopathological analysis of muscle sections of both polluted sites showed edema, splitting of muscle fibers, hyalinized muscle fibers, fatty tissue, necrosis and infiltration of lymphocytes. From the above, we can conclude that the contaminated environment of fish could cause detrimental effects on fish tissues and immune system causing great economic losses for the natural resources.