The hepatoprotective potential of hispolon against carbon tetrachloride (CCl(4))-induced liver damage was evaluated in preventive models in rats. Male rats were intraperitoneally treated with hispolon or silymarin once daily for 7 consecutive days. One hour after the final hispolon or silymarin treatment, the rats were injected with CCl(4). Administration with hispolon or silymarin significantly decreased the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in serum and increased the activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione (GSH) content and decreased the malondialdehyde (MDA) content in liver compared with CCl(4)-treated group. Liver histopathology also showed that hispolon reduced the incidence of liver lesions induced by CCl(4). In addition, hispolon decreased nitric oxide (NO) production and tumor necrosis factor (TNF-α), inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) activation in CCl(4)-treated rats. We also examined the involvement of matrix metalloproteinase (MMP)-9 in the development of CCl(4)-induced liver damage in rats. Hispolon inhibited the expression of MMP-9 protein, indicating that MMP-9 played an important role in the development of CCl(4)-induced rat liver damage. Therefore, we speculate that hispolon protects rats from liver damage through their prophylactic redox balancing ability and anti-inflammation capacity.