Despite being one of Egypt's most significant fish production resources, Lake Manzalah (Northeast Egypt) is subject to substantial inputs of pollution from domestic, agricultural and industrial sources. The liver and gonads of Oreochromis niloticus were evaluated for histological and ultrastructural alterations in the current study to monitor the possible effects of Lake Manzalah pollution at two different areas, (A) near Hadous drain and (B) near the Bahr El-Baqar drain during autumn and spring seasons. Heavy metal concentrations in water, sediment, and fish tissues were assessed. The results showed that Fe, Mn, and Ni levels were greater than the standard allowable values in area B compared to area A, and in autumn rather than spring. Both studied areas showed heavy metal deposition in O. niloticus tissues with greater values in autumn, compared to spring. The maximum concentration of the heavy metal in tissues was found in the fish liver of area (B) in autumn. In the autumn and area B, there were significant histopathological and ultrastructural damages to the liver and gonads. It was concluded that the noted biomarker responses were possible indicators of health deterioration in Lake Manzalah fish populations. Long-term monitoring is therefore required to assess the eco-health of the Manzalah Lake ecosystem by using bio-indicator species such as Oreochromis niloticus, which offer accurate, dependable measures of environmental quality.