Proanthocyanidin was shown to exert anti-inflammatory, antioxidant, hepatoprotective properties, and anticancer activity. This study was done to investigate the protective effects of Proanthocyanidin on Diethylnitrosamine induced hepatocarcinogensis in rats. Fourty five male albino rats were divided into three groups. Group Ӏ: (normal control group): rats administered distilled water only. Group II: rats received Diethylnitrosamine (200 mg/kg b.wt/i.p), 2 weeks later rats received (2 ml/kg b.wt) Carbon tetrachloride (CCl4)  orally at 1:1 dilution in corn oil as a promoter of carcinogenic effect. DEN and CCl4 injections were repeated once again after 1 month from the first DEN injection. Group III: rats received DEN+CCl4 then treated with proanthocyanidin at a dose of (100 mg/kg b.wt/orally) dissolved in DMSO 7% for 6 weeks. All animals were sacrificed after the end of experiment. DEN induced HCC showed significant increase in hepatic marker enzymes (ALT and ALP), total bilirubin and alpha fetoprotein (AFP) with marked decrease in serum albumin concentration. Also, the results of molecular analysis in liver tissue revealed significant up-regulation in TNF-α gene expression level. Conversely, down-regulation in tumor suppressor gene p53 and Cyp2E1 gene expression compared with control group. Treatment with proanthocyanidin to DEN induced HCC protects the liver cells from damage by regulating the biochemical parameters. The obtained results suggest that proanthocyanidin can inhibit the proliferation of HCC cells through inducing tumor cell apoptosis via activation of the p53 pathway and detoxification enzyme Cyp2E1 and inhibition of TNF-α overexpression. Proanthocyanidin may thus be used as a potentially promising agent to inhibit HCC cell proliferation and may be a novel natural product for the management treatment of HCC.