Abstract: Background and Objective: Hepatocellular carcinoma (HCC) is the major threat to the human health and it has got 6th rank among all types of cancers and 3rd leading cause of cancer related death. The HCC patients have high mortality rate. Resveratrol (natural phenol) participate in a significant way in the formation of the cell membrane and also play a significant role in functioning of membrane fluidity and proteins. This study was aimed to examine the anticancer effect of resveratrol (RT) against diethylnitrosamine (DEN) induced HCC in Wistar rats. Materials and Methods: For the current experimental study, the Wistar rats were used and an intraperitoneal dose of DEN (200 mg kg–1) was given to them for the induction of HCC. The rats received various doses of RT for 22 weeks. The progressions of serum biomarkers and macroscopical components of hepatic tissue were used to access the prophylactic effects. The antioxidant parameters, cancer preventive agent status and apoptosis mechanism were reviewed to scrutinize the possible mechanism. Results: The RT treatment significantly (p<0.001) altered the hepatic nodules, body weight and hepatic, antioxidant, non-hepatic parameters in a dose-dependent manner. The macroscopical observation exhibited the hepatic nodules in DEN-induced rat’s liver and dose-dependent treatment RT significantly reduced the formation of hepatic nodules and decolourization of tissue. Curiously, the expression of β-arrestin-2, Bcl-xal and Bcl-2 were significantly (p<0.001) reduced and expression of caspase-3 and Bax was significantly (p<0.001) increased at the dose-dependent manner of RT treatment. Conclusion: On the basis of result, the authors concluded that the RT exhibited the defensive effect against the DEN-induced HCC that might be due to antioxidant effect and actuation of apoptosis.