Polyethylene glycol (PEG) was used for a wide range of medical and biological applications. The health problems that PEG can cause is the conversion of alcohol dehydrogenase by metabolic oxidation into oxalate. Moringa oleifera contains about 46 antioxidant compounds such as β-carotene and various phenolics. Previous studies did not report enough data on the hepatotoxicity of polyethylene glycol and the protective role of Moringa oleifera. Therefore, the current study was conducted to address this affair. Male rats were split for six set (six each group): control group 1, MOLE (200 mg/ kg) group 2, PEG (50 mg/kg) group 3, MOLE plus PEG (50 mg/kg) group 4, PEG (100 mg/kg) group 5, and MOLE plus PEG (100 mg/kg) group 6. Rats administered orally daily for 45 days. The obtained results showed that treatment with both doses of PEG caused significant increase in DNA breakages, TNF-α, IL-6, TBARS, and NOx comparison to group 1. While, both doses of PEG caused significant suppressed expression of PGC-1α and mtTFA, the p53 level, catalase, GR, and GSH were decline, as compared with group 1. It was concluded that the co-supplementation with MOLE caused significant hepatoprotection against PEG- induced liver toxicity at all levels.