The present research was planned to assess the harmful effects of heavy metals as well as antioxidant alterations of Oreochromis niloticus collected from two polluted fish farms located in Abbassa and Manzala (areas A and B, respectively) in Egypt. They were compared with reference site in central laboratory for aquaculture researchers during the summer season, 2020. A total number of 75 fish collected from all sites was subjected to clinical, postmortem, and bacteriological examination. Water parameters, as well as heavy metals (arsenic, manganese, and nickel) in water, serum, and tissues (muscle, gills, and liver), were evaluated. In addition, antioxidant enzymes (SOD and CAT) and (MDA) were assessed in the serum of O. niloticus. Bacterial isolates, Aeromonas hydrophila, were identified in fish at both localities, and the recorded mortality rate was about 30% and 5% in areas A and B, respectively. The levels of As in water samples from both polluted areas were higher than the permissible limits. In addition, serum of O. niloticus showed a significant decrease in the concentrations of Ni in both polluted areas. In addition, a significant decrease in the mean levels of Ni and As was found in the gills and muscles of O. niloticus in both polluted areas.  Moreover, a significant decrease in CAT, combined with a significant increase of SOD activities was observed in polluted area A.