Materials on the nanoscale are increasingly being targeted to cancer cells with great specificity through both active and passive targeting. In the current study, the potential therapeutic effect of the newly synthesized Zinc nanoparticles coated with Gallic acid (Zn-GANPs) against hepatocellular carcinoma (HCC) -induced in rats were evaluated. Forty rats were divided into four equal groups, group 1: normal control, group 2: received diethylnitrosamine (DEN) (20 mg/Kg b.wt, 5 times per week for 8 weeks), group 3: received Zn-GANPs (20 mg/kg b. wt./day, i.p) from the onset of the 9th week till the end of the experiment (13 weeks), group 4: DEN + Zn-GANPs treated group: Rats were received DEN as group (2) and subsequently treated with Zn-GANPs as group (3) till the end of the experiment (13 weeks).Blood samples and liver tissue specimens were collected for biochemical analysis and histopathological examination. The obtained results revealed that in HCC-induced rats serum aspartate aminotransferase (AST) activity, total bilirubin and creatinine levels were increased, while total protein, albumin concentrations and liver catalase activity were significantly decreased as compared with control normal group. Administration of Zn-GANPs to HCC-induced rats non-significantly reduced serum AST activity, total bilirubin and creatinine concentrations. However, serum total protein and albumin levels were non-significantly increase and liver catalase activity was markedly increased in Zn-GANPs treated liver cancer group. Ameliorative effect of Zn-GANPs was appreciated with the histopathological alterations observed in DEN groups. These results suggesting the efficacy of Zn-GaNPs administration as an anti-HCC Cytotoxicity HCC HepG2 cell line Liver function tests Zn-GANPs