Spinach, (Spinacia oleracea L.) is a popular vegetable. The hepatoprotective activity of the ethanolic extract of the leaves of spinach (EESO) was studied against carbon tetrachloride (CCl4)-induced oxidative stress (OS) and liver injury in rats. Pretreatment of rats with EESO, at 250 and 500 mg/kg body weight for 21 consecutive days significantly prevented the CCl4-induced hepatic damage as indicated by the serum marker enzymes (SGOT, SGPT, ALP and GGT) and bilirubin levels. Parallel to these changes, the leaves extract also prevented CCl4-induced OS in rat liver by inhibiting lipid peroxidation (LPO) and restoring the levels of antioxidant non-enzymatic biomarker, such as total protein (TP) and non-protein sulfhydryl (NP-SH) in liver tissue. The biochemical changes were consistent with the histological findings of the liver tissue suggesting marked hepatoprotective effect of the leaves extract in a dose-dependent manner, besides, a significant reduction was also observed in pentobarbital-induced sleeping time in mice. The results of spinach extract were comparable to that of silymarin. The protective effect of the EESO against CCl4-induced acute hepatotoxicity could be attributed to the potent antioxidant constituents of the spinach.