Background: Hepatocellular carcinoma (HCC) is the utmost familiar form of liver distortion, a prevalent high incidence that ensures the fifth most recurrent primary malignancy around the world. Objectives: To investigate the chemopreventive and apoptotic effect of vernodalin in diethylnitrosamine (DEN) induced HCC. Materials and Methods: Rats were distributed into four sets of experimental animals every six rats: control group, DEN alone, DEN + vernodalin, (10 mg/kg bw), and vernodalin (10 mg/kg bw) alone. The analysis was conducted to measure the liver and body weight. The assay was designed to analyze hepatic toxic markers, antioxidants, lipid peroxides, and inflammatory cytokines, in addition, histopathology and western blot analysis were also conducted. Results: DEN with vernodalin diminished weight of the body and antioxidant level whereas raised the liver weight, toxic marker concentration, oxidative stress and cytokines. Vernodalin also prevents oxidative stress, lipid peroxides level, toxic markers, pro-inflammatory, and cytokines. Vernodalin suppressed the P13K/AKT signaling that enhances apoptosis and maintains the morphology of cells. Conclusion: The results indicate that vernodalin exerts a promising chemopreventive and apoptotic natural agent for DEN-induced HCC in rats.