The goal of this study was to assess the harmful effects of heavy metal accumulation on Clarias gariepinus (catfish) in two different polluted areas in the Al Sharkia governorate and assess the impact on oxidative stress and histological changes. The results revealed a highly significant difference in heavy metal levels in the water and inside fish tissues (liver and gonads) between the two sites. The total prevalence of parasitic infection was at the highest percentage in area B, in addition to severe histopathological damage to the liver and the gonads. Findings show that the total prevalence of parasitic infection is associated with uptake of metals, depleted antioxidant activity, and incidence of lipid peroxidation in tissue.