Aquaculture fish face stresses include temperature, ammonia levels, water salinity, and dissolved oxygen. In order to sustain finfish output, it is necessary to assess the impact of unexpected weather on their performance. Thus, this study examined whether Nile tilapia's vitamin E intake reduces heat and salinity stress. After 56 days of feeding a diet enriched with vitamin E at 0, 150, 300, 600, and 1200 mg/kg, Nile tilapia were split into two groups: one was given a 28 g/L salinity increase, and the other to a temperature increase of 36 °C. Heat and salinity stress increased cortisol, glycose AST, ALT, triglycerides, and total cholesterol while decreasing albumin, globulin, and protein. Fish diets with vitamin E significantly improved the parameters above before and after heat and salinity stress. However, heat and salinity stress inhibited superoxide dismutase, catalase, glutathione peroxidase, nitrous oxide, lysozyme, phagocytosis, and immunoglobulin, reducing antioxidant activity and immunological responses. The Nile tilapia diet's vitamin E content increased antioxidant activity and immunological response before and after stress. Heat and salinity stress increased lipid peroxidation (malondialdehyde), but vitamin E-fed fish had lower values than controls. In addition to mild hepatocyte degeneration, pyknosis, and hepatic central vein congestion, heat and salinity stress cause severe vascular congestion with gill lamellar epithelium degeneration, sloughing, and primary filament congestion. In Vit E-treated groups, histomorphology returned to normal. Results showed that vitamin E at 1200 mg/kg in the Nile tilapia diet may be an effective antioxidant immunostimulant against environmental stressors like heat and salinity.