Hepatocellular carcinoma (HCC) is still a main cause of fatality for individuals with chronic liver illnesses, according to statistical analyses of cancer. Gallic acid (GA) is among the most probable polyphenols which possess several pharmacological effects as antioxidant, anti-Inflammatory, apoptotic and antitumor activities. Therefore, the objective of this study is to evaluate the potential therapeutic and anti-cancerous effect of GA on a rat model of HCC. Thirty rats were segregated equally into three groups. G1 (Normal control): Rats given saline as a vehicle. G2: (HCC non -treated) HCC was induced via utilizing diethylnitrosamine (DEN) injection (200 mg/kg b.wt) intraperitoneal, then two weeks after DEN injection, rats were given 3 weekly successive doses of CCl4 diluted with corn oil at 1:1 proportion (3 ml/kg b.wt) orally to boost the carcinogenic impact. DEN and CCl4 administrations were repeated after a period of 5 weeks. G3: (HCC+GA treated): 15 weeks after HCC induction, treatment with GA (100 mg/kg b. wt.) given orally and continued for six weeks. The results showed significant upregulations in liver microRNA-221 and TGF-β1, with obvious down-regulation of (Nrf2 and Bcl-2) and insignificant downregulation of caspase 3 gene in HCC-induced rats. GA treatment exhibited significant decline in ALT, AST and ALP hepatic enzyme markers with downregulation of TGF-β1, microRNA-221 and upregulation of Nrf2, Bcl-2 and caspase 3 gene expression. In conclusion, GA reduces liver preneoplastic lesions development and has a helpful therapeutic impact against liver cancer, inhibiting growth promoting oncogene and increasing apoptosis.