This study to evaluate the protective effect of Vitamin E (1mg/kg, P.O. once daily) on Memantine adverse effects (0.36mg/kg, P.O. once daily) and its effect on liver, kidney, blood and antioxidant enzymes for three weeks. Then tissue and blood samples were collected on 1st, 2nd and 3rd weeks post-treatment to assess the protective effect of Vitamin E. Our results indicated that Vitamin E has hepato-nephro-protective and there was a decrease in the elevation of liver enzymes caused by Memantine like ALT, AST and ALP and kidney parameters like creatinine, urea and uric acid, and there was a normalize in all blood parameters which decrease by Memantine  and finally there was a significant increase in antioxidant enzymes like CAT, SOD, GPX and a significant decrease in MDA, beside showing decrease in hepatic steatosis (arrowhead) and decrease in  the apoptotic and necrotic cells mostly within the centrolobular caused by Memantine administration, as demonstrated by hepatic histopathology. Also, showing decrease in tubular basophilia, and decrease in interstitial nephritis (arrow indicated leukocytic infiltration), as showed by kidney histopathology. Therefore, Vitamin E should be taken with Memantine to decrease its side effects