Hepatocellular carcinoma (HCC) is the second most fatal cancer, caused by either factors outside the body or even with hereditary or genetic changes. The potential chemotherapeutic effect of ginger extract (GE) and ginger nanoparticles (GNPs) against diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) induced HCC in rats was evaluated. HCC was induced via utilizing DEN injection (200 mg/kg b. wt/ I.P), then 2 weeks later of DEN injection rats received 3 weekly successive doses of CCl4 diluted with corn oil at a ratio of 1:1(3ml/kg b.wt) orally to boost the carcinogenic impact. The administration of DEN and CCl4 was repeated after a period of 5 weeks. 15 weeks after HCC induction, treatment with GE (300mg/kg b.wt/day) and GNPs (50mg/kg b.wt/day) were given orally and continued for six weeks. Twenty-four male rats were separated into four equal groups. Group 1 (normal control): Rats received saline as a vehicle, Group 2: (DEN/CCl4 induced HCC), Group 3: (DEN/CCl4 +GE), and Group 4: (DEN/CCl4 +GNPs). The results revealed significant upregulation in liver microRNA-221 with obvious down-regulation of Nrf2 and Bcl-2 and insignificant downregulation in caspase 3 gene in HCC-induced rats. GE and GNPs treatment exhibited a significant decrease in liver marker enzymes with downregulation of microRNA-221 and upregulation of Nrf2, Bcl-2 and caspase 3 gene expression. These findings suggested that GE and GNPs have a beneficial therapeutic effect against liver cancer, inhibiting growth-promoting oncogene and increasing apoptosis.