Propolis has several biological/pharmacological properties. The current study investigated the potential hepatoprotective benefits of propolis in CCl4-treated mice. Three groups of male BALB/c mice (n=15/group) were used in the current study: group I comprised control mice, groups II was intraperitoneally injected with CCl4 (1.0 mL of 10% CCl4 dissolved in olive oil/kg body weight, twice/week for six weeks) for inducing liver fibrosis, group III was treated with CCl4 as in group II and then supplemented orally with the ethanol-soluble derivative of propolis (100 mg/kg body weight/day) for additional four weeks. The antifibrotic effects of propolis were assessed by histological analysis, western blotting, flow cytometry, and ELISA. The results indicated that the CCl4-treated mice exhibited histopathological alterations in the liver architecture with an increase in the numbers of Kupffer cells, a significant increase in the lymphocytes apoptosis and in the plasma nitric oxide, reactive oxygen species, C-reactive protein, and platelet derived growth factor levels, and a significant decrease in the plasma total glutathione level, as compared with the control group. The liver of CCl4-treated mice also exhibited a significant increase in the expression of collagen and survivin, upregulation of signal transducer and activator of transcription 3 (STAT3) phosphorylation, and downregulation of STAT5 phosphorylation. Interestingly, propolis abrogated significantly the hepatic collagen deposition, inflammatory signals, and oxidative stress, and improved the hepatic architecture in CCl4-treated mice nearly to the normal architecture observed in the control mice. In conclusion, our findings demonstrate the potential hepatoprotective effects of propolis in alleviating the liver fibrosis.