Objective: To evaluate the effect of MESA on NDEA induced hepatocellular carcinoma on Sprague Dawley rats. Methodology:Semecarpus anacardium commonly known as ‘marking nut tree’ is a rich antioxidant and in Ayurveda it has been used for treatment of various forms of cancer. Methanolic extract of leaves of Semecarpus anacardium (MESA) was studied for its potential antioxidant property both in vitro and in vivo. NDEA 200 mg/kg, single i.p was the hepatocarcinogen while 200 mg/kg and 400 mg/kg of MESA was administered daily orally for 12 weeks. Protective effect of MESA was evaluated by measuring biochemical parameters like SGOT, SGPT, ALP and LDH. Alpha fetoprotein test was performed and histopathology changes of livers were assessed. Results: Preliminary phytochemical study revealed the presence of flavonoids, tannins, steroids, alkaloids, glycosides and vitamin C. MESA restored the level of antioxidants near to normal and reduced the elevated serum level of SGOT, SGPT, AST, LDH and AFP. The histopathology changes i.e. necrosis, widened sinusoids, elevated inflammatory cell infiltrate were partly or fully prevented in animals treated with the extract. Conclusion:The result of the present study indicates MESA to be rich in antioxidants and its active constituents mediated the free radical scavenging activity. 400 mg/kg extract showed promising effect in management of primary liver cancer.