Hepatocellular carcinoma (HCC) the second most fatal cancer, caused by either factors outside the body or even with hereditory or genetic changes. The potential chemotherapeutic effect of ginger extract (GE) and ginger nano particles (GNPs) against diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) induced HCC in rats was evaluated. Rat HCC was induced 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 (3ml/kg b.wt) orally diluted with corn oil at a ratio of 1:1 to boost the carcinogenic impact. The administration of DEN and CCl4 was replicated 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 no drugs, Group 2: (DEN/CCl4), Group 3: (DEN/CCl4 +GE), and Group 4: (DEN/CCl4 +GNPs).The results revealed significant rise in serum ALT, AST and ALP activities and upregulation in liver microRNA-221 with obvious down-regulation of Nrf2 and Bcl-2 and insignificant down regulation in caspase 3 gene in HCC-induced rats. GE and GNPs treatment exhibited significant decrease in liver marker enzymes with downregulation of microRNA-221 and upregulation of Nrf2, Bcl-2 and caspase 3 gene. These findings suggested that, GE and GNPs has a beneficial chemopreventive effect against liver cancer, inhibiting growth promoting oncogene and increasing apoptosis, as well as protects the liver by lowering oxidative damage and inflammation.