This study was carried out to assess the accumulation and distribution of heavy metals (Pb, Hg, Cd, and As) in Lake Maryout. The impact of heavy metal contaminations was also assessed in different target tissues (gills, liver, kidney, and muscles) of Clarias gariepinus (C. gariepinus) using physiological and histopathological parameters in the Main Basin and a relatively clean area (South-west Basin). Heavy metals concentration in water showed that Main Basin had the highest levels of Pb, Hg, As and Cd metals. The abundance of heavy metals in different fish organs; gills, livers, kidney, and muscles followed the order: Pb> Cd >As >Hg. Fish muscle compared to other tissues; usually, contain the lowest level of metals. Physiological alterations showed a significant severe anaemia, leukocytosis, neutrophilia, lymphopenia, and monocytosis was detected in fish collected from Main Basin in comparison to South-west Basin. Moreover, a significant increase in serum ALT, AST and creatinine were observed, while serum urea showed insignificant decreased in fish collected from Main Basin in comparison to South-west Basin. Histopathological alterations of gills showed lamellar fusion and hypertrophy of epithelial cells. Liver samples included necrosis of hepatocytes. Finally, kidney pathologies demonstrated the glomeruli appeared shrunken, desquamated, and vacuolated and often destroyed tubular epithelium. The mean fish intake of adults provides exposure to metals that fall within the accepted standards for the safe intake. It is recommended that the situation need a scientific method of detoxification to improve the health of this Lake and economic fish.