The chitosan-caffeic acid (CCA) conjugate shows a hepatoprotective effect against oxidative stress-induced hepatic damage in cultured hepatocytes. The objective of this study is the verification of the hepatoprotective effect of the CCA in vivo against ethanol-induced liver injury in mice. The administration of ethanol resulted in the increase of the serum-aminotransferase activities (AST and ALT), triglycerides, total cholesterol, and lipid peroxidation. The CCA co-administration, however, significantly (p<0.05) ameliorated these serum biomarkers. The antioxidant-enzyme activities in the liver tissue, including those of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), were significantly decreased by a chronic ethanol administration, whereas the hepatic lipid-peroxidation level was increased. Moreover, the chronic ethanol administration elevated the gene expression of pro-inflammatory cytokines such as tumor-necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the liver tissue. The CCA co-administration, however, significantly (p<0.05) increased the activities of the SOD, CAT, and GPx and caused the down-regulation of the TNF-α- and IL-6-gene expressions in the liver tissue. An histopathologic evaluation also supported the hepatoprotective effect of the CCA against ethanol-induced hepatotoxicity in the mice.