The present investigations were undertaken to evaluate the Nephroprotective effect of the ethanol extract of Salacia fruticosa Heyne ex Lawson against Acetaminophen-induced nephrotoxicity and oxidative stress in rats. Salacia fruticosa (Hippocrateacea) have been used in Ayurvedic, Siddha and Folklore for various diseases in India. The extent of renal damage and effect of ethanol extract of Salacia fruticosa (EESF) were assessed by various biochemical parameters in the experimental rats. Histopathological changes in the renal tissues of experimental rats were also studied. The administration of effect of ethanol extract of Salacia fruticosa at dose levels of 250 and 500 mg/kg/b.w orally were decreased in levels of blood Urea, uric acid, creatinine when compared to APAP treated rats. The antioxidant studies reveal that the rats treated with EESF were increased the levels of renal SOD, CAT, GSH and GPx, however the level of MDA were reduced as compared with APAP induced rats. Apart from these, histopathological changes also reveal that the protective nature of ethanol extract of Salacia fruticosa against acetaminophen induced necrotic damage of renal tissues. In conclusion, this study demonstrates that the protective effect of ethanol extract of Salacia fruticosa from APAP induced nephrotoxicity in rats and the results suggested that the possible mechanism of this effect may be due to free radical-scavenging and antioxidant activity.