Premna esculenta Roxb. (family Verbenaceae) is a shrub used by the ethnic people of Chittagong Hill Tracts of Bangladesh for the treatment of hepatocellular jaundice. The present study was done to evaluate the hepatoprotective and the in vivo antioxidant activity of ethanolic extracts of leaves of the plant in carbon tetrachloride-induced liver damage in rats. Hepatotoxicity was induced in rats by i.p. injection of CCl4 diluted with olive oil (1:1 v/v; 1 mL/kg body weight) on alternate days for 7 days. After 7 days of pretreatment of test extracts, the biochemical markers such as Serum Glutamate Oxaloacetate Transaminase (SGOT), Serum Glutamate Pyruvate Transaminase (SGPT), Alkaline Phosphatase (ALP), total protein, and albumin were estimated followed by the measurement of liver cytosolic antioxidant enzymes such as superoxide dismutase, catalase, and peroxidase. The data were analyzed using one-way analysis of variance (ANOVA) followed by Dunnett's t-test. The extract both at the doses of 200 and 400 mg/kg p.o. significantly (P < 0.001) reduced the elevated levels of SGPT, SGOT, ALP and increased the reduced levels of total protein and albumin compared to the CCl4-treated animals. The extracts also showed a significant (P < 0.001) increase in the reduced levels of superoxide dismutase (SOD), catalase, and peroxidase. The effects of the extracts on these parameters were comparable with those of the standard, silymarin. The findings of the study indicate that the leaf extract of P. esculenta showed a potential hepatoprotective activity and the protective action might have manifested by restoring the hepatic SOD, catalase, and peroxidase levels. The results justify the traditional use of this plant in liver disorders.