The good growth performance of tilapia species has been recorded in nearly isosmotic salinities. The present study aimed to evaluate the effect of salinity on the structure of Coptodon zillii, being one of the most salinity tolerant tilapia species. Qaroun Lake looses water by evaporation which affects the water levels of the lake and its salinity, recently was subjected to a sharp rise in salinity degrees, which led to a sharp decrease in the rate of fish production. Histological, histochemical, immunohistochemical and genetic studies are used as accurate tests for evaluating the effects of salinity in Tilapia fish. The results showed that fish obtained from Wadi El Rayan1 showed semi typical structure of gill and liver, others from Wadi El Rayan2 showed slight deviations from normal one, on the contrary, samples from Qaroun lake exhibited a series of severe variations; histological changes as severe degeneration, necrosis, edema, hemorrhage, and Hemosidrin, as well as, a reduction in the distribution of carbohydrates, an increase of collagen amount and a strong caspase-3 expression in gill and liver cells. Moreover, the genetic results indicated a clear sensitivity of prolactin gene to different degrees of salinities, which can possibly control the euryhalinity capacity of C. zillii. All of these results demonstrated the strong effect of the high elevation of salinity on fish production and the histological structure of the internal tissues of one of the most important fish in Egypt.