Background and objective Amethopterin (AM), like most chemotherapy medications, causes cellular generation of oxidative stress. In Iranian traditional medicine, Sumach is widely used owing to its antioxidant properties. In this study, the authors aimed to assess the probable antioxidant, antiapoptogenic, and therapeutic effects of Sumach extract on liver tissue and hepatocytes against hepatic degeneration induced by AM as a chemotherapy drug. Materials and methods A total of 64 rats were grouped (n=8), including (1) control, (2) AM (20 mg/kg), (3-5) Sumach (75, 100, 150 mu g/ml), and (6-8)- AM+Sumach. Hydroalcoholic extract of Sumach seeds was prepared. Treatments with Sumach extract were applied intraperitoneally daily for 28 consecutive days. Nitrite oxide was measured by Griess assay. Ferric reducing ability of plasma (FRAP) and malonaldehyde test were used to measure total antioxidant and lipid peroxidation levels, respectively. Hepatocyte apoptotic index was analyzed via tunnel test. The expression level of p53 and Bax genes was measured by real-time PCR. Furthermore, liver enzymatic function, histopathological changes, and morphometric alterations were examined. Results and conclusion Antioxidant values, p53 and Bax genes' expression, nitrite oxide, enzymes, and morphometrical features were increased significantly (except FRAP levels, decreased) in AM group as compared with the control group (P<0.01). Besides, the evaluated parameters were all significantly reduced (except insulin and FRAP levels and Bcl2 gene expression, which were increased) in SMGC and diabetic+SMGC groups in comparison with the diabetic group (P<0.05). Moreover, evaluated parameters were significantly reduced in Sumach and Sumach+AM groups (except FRAP level, which is increased) compared with the AM group (P<0.01). According to the acquired data, Sumach through its antiapoptogenic and antioxidant features is able to eliminate hepatotoxicity induced by AM administration, which leads to restoration of histopathological liver changes.