Methotrexate (MTX) is known to cause damage to the liver, leading to hepatic dysfunction. The present work aimed at studying the protective role of the three natural antioxidants; propolis, silymarin or ginger in modulating the adverse effect of methotrexate on the liver cells of rat. In the present study forty animals were used. The animals were divided into five groups as follows: Group 1 (G1): rats were administered saline and served as control; group 2 (G2): rats received a daily dose of 200 mg/kg body weight ginger extract; group 3 (G3): rats received a daily dose of 200 mg/kg body weight propolis; group 4 (G4) rats received a daily dose of 200 mg/kg body weight silymarin. All treatments were orally administered for 21 days to rats in groups II, III and IV before methotrexate administration. On day 21, eight rats were injected intraperitoneally with a single dose of methotrexate (20 mg/kg body weight) and served as group 5 (G5). On the same day, the single dose of MTX was also given to all rats, except the control group. Treatments were continued for 5 consecutive days in groups II, III and IV. All the animals were sacrificed on day 25. The animals were sacrificed and tissue samples taken from the liver were processed for both light microscopy and transmission electron microscopy. Light microscopic examination of methotrexate revealed dilatation of the sinusoids, fatty changes, karyolytic or pyknotic nuclei and vacuolated cytoplasm. Ultrastructural examination of liver cells from MTX-treated animals revealed obvious injuries to the cell fine structure. The cytoplasm was ill-defined and lost its normal differentiation. Treatment with the three antioxidants reduced the liver cellular changes. Electron microscopic study supported the histopathological study. Moreover, the three materials reduced the DNA damage of liver cells as observed from the significant decrease in the Comet assay (tail length and damaged DNA%). All these results suggest the efficacy of the three used materials which may be attributed to their antioxidant properties. Propolis was found to be more effective than the other two antioxidants.