This study investigated the preventive effect of Dendropanax morbifera leaf extracts (DMLEs) drew out with water, 30, 50 and 70% ethanol against alcohol-induced hepatotoxicity in vitro and vivo. The 3-(4,5-dimethylthiazol-2-yl)-2,5-dipenyltetrazolium bromide (MTT) assay was performed to assess cytotoxic activity of DMLEs, and the half-maximal inhibitory concentration (IC50) ranged between 1.11 and 2.08 mg/mL on Hep3B cells. In preventing ethanol-induced-hepatotoxicity on Hep3B cells, 30 and 50% ethanol DMLEs were significantly effective compared to the 5% ethanol treatment control. In addition, the 30% ethanol DMLE was orally provided to rats 30 min prior to the administration of ethanol (3 mL/kg body weight). At 1, 3 and 5 h after ethanol treatment, the plasma levels of ethanol and acetaldehyde were determined. The 30% ethanol DMLE effectively decreased the plasma ethanol levels during 5 h but increased the plasma acetaldehyde levels until 3 h and then significantly decreased at 5 h, as compared to the control. These results indicate that the 30% ethanol DMLE possesses a potent preventive effect against ethanol-induced liver toxicity in Sprague-Dawley rats.