OBJECTIVE: This study examined the impact of menthol, a natural monoterpene, on diethylnitrosamine (DEN)-induced molecular and histopathological changes in the livers of male mice. MATERIALS AND METHODS: Forty male mice were divided into four groups: Control, Menthol (M), DEN, and DEN-M. The DEN and DEN-M groups received an intraperitoneal injection of DEN (25 mg/kg) at the age of 14 days. The M and DEN-M groups were also given menthol (50 mg/kg, three times a week for six months) via gavage. The expression of genes related to liver carcinoma was analyzed using real-time PCR. Subsequently, the liver tissue was microscopically examined following staining with hematoxylin-eosin. RESULTS: After one month, menthol reduced the infiltration of inflammatory cells in the liver tissue of mice injected with DEN. It also prevented the increase in the expression of alpha-fetoprotein () (p<0.001), programmed cell death 6 (p<0.05), hypoxia-inducible factor-1 alpha () (p<0.001), and vascular endothelial growth factor () (p<0.001) in DEN-M animals compared with DEN group. After six months of session, the expression of (p<0.05), (p<0.05), secreted frizzled-related protein 1 (p<0.001), and catenin beta 1 (p<0.01) was lower in group DEN-M compared with group DEN. Menthol also partially prevented DEN-induced various histopathological changes in the liver after six months of treatment. CONCLUSION: We concluded that menthol inhibits Wnt signaling and suppresses the expression of and in the liver of DEN-injected mice. It is probably a suitable option for the prevention and treatment of hepatocellular carcinoma.