Liver cancer is known as a high morbidity and low survival disease all around the world. This cancer is the most traumatic disease because it affects the major organs of the body. Valproate is a branched-chain fatty acid, which has been widely used as an antiepileptic in liver cancer therapy. However, this drug can induce fulminant liver failure in patients treated with it. Herein, we prepared the desired ZnO and Ag-doped ZnO nanostructures via a simple and efficient method and characterized them with XRD and FESEM. Then, we investigated cytotoxicity potential of ZnO and Ag-doped ZnO nanoparticles on a well-known human liver cell (HepG2) via trypan-blue dye exclusion assay with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The performed experiments show that the prepared ZnO nanoparticles have a significant concentration (20 g/ml) and time-dependent cytotoxicity on the examined cell lines after 24 h and proved damage of the cancer cells in this time interval. Moreover, Ag-doped ZnO also exhibits better cytotoxicity potential compared to bare ZnO. Therefore, ZnO and 0.5% Ag-doped ZnO nanoparticles may have less cytotoxic effects on the liver and can be applied as suitable candidates parallel with the existing valproate drug.