Background: Mortality due to HCC is the fourth most common cause of mortality among Americans. Furthermore, HCC is most common in Asia and Africa, where hepatitis C and B are prevalent. Hepatocellular cancer therapy relies heavily on chemotherapy, from between the chemotherapy medicines cisplatin and doxorubicin, two of the most widely prescribed for the treatment of liver cancer. Aim of the study: To determine the cytotoxicity of cisplatin and doxorubicin in HepG2 cell line by the methyl thiazole tetrazolium (MTT) assay and assess nitric oxide (NO) levels and their significance as oxidative status markers in the progression of HCC. Material and Methods: HepG2 cells were incubated with different drugs concentrations. The half-maximal inhibitory concentration (IC50) values were determined the methyl thiazole tetrazolium (MTT) for cisplatin and doxorubicin. Results: IC50 values for HepG2 were found for doxorubicin and cisplatin (1.679 μg and 4.323 μg ), respectively. The NO levels in the HepG2 cell line treated with Cisplatin and Doxorubicin were measured. We found limited elevated NO levels after treating HepG 2 cell lines by doxorubicin. Moreover, there was significant inhibition in NO levels after treating with cisplatin. Conclusion: The findings suggest that nitric oxide levels can be utilized as a new diagnostic marker with predictive value for HCC.