Hepatocellular carcinoma (HCC) is a lethal disease, and in HCC advanced stages, there is limited therapeutic efficacy. HCC results in a complication of fibrosis or cirrhosis. In this study, the protective effect of curcumin and selenium versus hepatocellular carcinoma caused by CCl4 in experimental animals was investigated. In all, 70 mice were divided into seven groups to study the effect of curcumin and selenium on CCl4 -induced hepatocellular carcinoma. After treatment time, different animal groups were sacrificed, serum and liver samples were collected and processed for assay of biochemical and molecular parameters. Our results showed that CCl4 administration induced various alterations such as significant elevation in the serum levels of ALT, AST, and hepatic contents of malondialdehyde (MDA), and depletion in the levels of antioxidant parameters. CCl4 induced apoptosis in the hepatic cells indicated by an increased level of p53, CD4, CD8, Bax, and Annexin V/PI in addition to significant decrease in the level of Bcl-2. Administration of curcumin and selenium restored this abnormal variation in these biochemical parameters to normal values. Our study addressed that curcumin or selenium may be helpful in the protection against liver damage induced by CCl4 . The hepatoprotective impact of curcumin or selenium might be mediated primarily by its potent antioxidant activity. PRACTICAL APPLICATIONS: Hepatocellular carcinoma (HCC) ranked third common cause of death, primary liver cancer. Exposure to CCl4 was found to induce significant hepatotoxicity, characterized by fibrosis, bile duct proliferation, cirrhosis, and reduced hepatic function The work was prepared to investigate the protecting capacity of curcumin, selenium alone, and in combination against HCC induced by CCl4 in the experimental animal model. This study proved the protective effect of curcumin and selenium, alone and in combination with each other, where curcumin showed multiple pharmacological activities, including anti-inflammation and antioxidant, and have an essential role in inhibiting the progression of HCC.