Methotrexate (MTX) is an effectively used drug in the treatment of cancer and inflammatory diseases but, its use is related with hepatotoxicity. Inulin with antioxidant properties has hepatoprotective effects. In this research, we assessed inulin effects on MTX-induced liver toxicity. 48 male mice were randomly assigned into 6 equal groups. Mice were Pre-treatment with inulin (100, 200 and 400 mg/kg) for 9 consecutive days, orally) and MTX (10 mg/kg, intraperitoneally) was received on the 7th, to 9th day. Blood and liver were collected to assess liver functional test in serum samples and Stress oxidative biomarkers, pathological changes, the expressions levels of apoptotic factors, such as, Bcl-2, caspase -3 and miR-122 in the mice liver. The results indicated that MTX administration induced marked liver damage and serums factors of all of the mice. Furthermore, there was a decrease in the Bcl2 and an increase in the caspase-3 activity and miR-122 expression compared to the control group. Instead, inulin Pre-treatment clearly improved these variations induced by MTX. Finally, our results revealed the new evidence that the hepatoprotective effects of inulin might be mediated via the modulations of apoptotic and oxidative stress factors.