The study aimed to assess the effect of crude melon fruits extract (Cucumis melo L.) on the plasma antioxidant capacity and oxidative stress markers in liver tissue of CCl4 -hepatoxicity in mice. The administration of melon extract at doses of 200 and 600 mg/kg during 7 days caused significant elevation of plasma antioxidant capacity using DPPH (36.66 ± 2.53, (46.80 ± 1.708%). However, the administration of extract did not exhibit a significant reducing power (0.545 ± 0.023 and 0.581 ± 0.051) at two doses, respectively compared with control (0.446 ± 0.021). Evaluation of MDA levels revealed that the doses of 200 and 600 mg/kg reduced the lipid peroxidation in liver (21.54 ± 3.519 and 26.62 ± 6.681 nmol/g tissue respectively) compared with control group (126.2 ± 17.9 nmol/g tissue). Furthermore, a significant impact on protein levels in the liver was observed at a dose of 600mg/kg with a value of 18.61 ± 1.885 mg/ml. The catalase activity displayed an important elevation with 583.8 ± 34.56 U/tissue at the dose of 600mg/kg. Additionally, there was a significant increase in glutathione levels (9.335 ± 0.2980 μmol/g tissues and 9.476 ± 0.3349 μmol/g tissue) at both doses respectively. The findings of this study highlight melons as a source of natural antioxidants with significant biological functions.