The hepatoprotective activity of Picrorrhiza rhizoma (PR) water extract was evaluated on carbon tetrachloride (CCl(4))-induced subacute hepatic damage, induced by subcutaneous injection of CCl(4) (0.15 mL/kg of body weight) in pure olive oil (7.92%, vol/vol) three times a week for 10 weeks. Animals were sacrificed 10 weeks after oral administration of PR extracts at 50, 100, or 200 mg/kg or silymarin at 100 mg/kg, which were administered simultaneously with CCl(4); changes in body weight, liver weight, and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were observed along with differences in liver histopathology and histomorphometry. In addition, liver malondialdehyde as an index for lipid peroxidation, hydoxyproline as an index for collagen synthesis, and protein content were determined. Ten weeks of CCl(4) injections caused subacute hepatic damage, featuring significantly less body weight gain and hepatic protein contents and higher liver weight, serum AST and ALT levels, and hepatic malondialdehyde and hydroxyproline contents with subacute hepatic damage-related histopathology of the liver. However, the CCl(4)-induced toxic effects were dramatically and dose-dependently inhibited by PR extract treatment. Thus oral administration of PR extracts significantly reduced CCl(4)-induced subacute hepatic damage in rats, probably by exerting a protective effect against hepatocellular necrosis via its free radical scavenging ability.