Lake Nasser ecosystem has undergone many changes that decline species diversity; the lakes' fisheries also have experienced a decrease during the last 10 years disturbing its prospect for sustainability. Therefore, this study aimed to evaluate and compare the effect of water contaminants on O. niloticus and S. galilaeus inhabiting different locations of Lake Nasser. Heavy metals (HM) accumulation in the liver, gills and muscles of both O. niloticus and S. galilaeus generally arranged in the following order; Fe˃ Mn˃ Zn ˃Cd˃ Cu. The metal pollution index (MPI) in the studied organs pursued the order:  liver > gill > muscle. While the hematological and biochemical indices of O. niloticus and S. galilaeus exhibited a significant alteration due to inhabiting stressful conditions. Moreover, pathological changes were observed in the muscles of both fish species from different sampling sites. The present study opined that S. galilaeus are more resistant than O. niloticus to environmental stress, while O. niloticus are more sensitive to aquatic pollutants. Moreover, there was a significant alteration in fish health, as well as adverse health effects, for habitual consumers of both fish species from S4.