Hepatocellular carcinoma (HCC) is still a main cause of fatality for individuals with chronic liver illnesses. Gallic acid (GA) is among the most probable polyphenols which possess several pharmacological effects as antioxidant, anti-inflammatory, apoptotic, and antitumor activities. The objective of this study was 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) were given saline as a vehicle. In G2 (HCC non-treated), HCC was induced via an intraperitoneal injection of diethylnitrosamine (DEN) (200 mg/kg b.wt), then two weeks later the rats were given 3-weekly successive doses of CCl4 (in corn oil at 1:1 proportion, 3 ml/kg b.wt) orally to boost the carcinogenic impact. DEN and CCl4 administrations were repeated after 5 weeks. In G3 (HCC+GA treated), 15 weeks after HCC induction, treatment with GA (100 mg/kg b. wt.) was 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 a 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.