In the current research, edible meat of freshwater clam Corbicula fluminea was subjected to enzymatic peptide extraction using animal protease. The clam protein hydrolysate (CPH) contained 45.78% essential amino acids and 44.97% hydrophobic amino acids and showed high alcohol dehydrogenase (ADH) activation in vitro. Four fractions were divided from CPH by ultrafiltration and further investigated for their hepatoprotective effects on alcohol-induced injury in mice. The 2.5-5 kDa fraction (CPH-3) showed the best effect for preventing hepatic damage caused by alcohol, as revealed by reduced serum aspartate transaminase (AST) and alanine transaminase (ALT) activities and hepatic malondialdehyde (MDA) level, the marked decrease in the hepatic triglyceride (TG) contents, and the enhanced hepatic ADH, aldehyde dehydrogenase (ALDH), and glutathione (GSH) activities. Furthermore, histopathology of CPH-3-treated mice showed less hepatic tissue damage compared to alcohol-or other CPHstreated mice. Hence, CPH-3 was further purified by consecutive chromatographic techniques with gel filtration and reversephase high-performance liquid chromatography. One hepatoprotective peptide, KKLAGFLRYYS (1330.68 Da), was identified by LC-MS/MS, which exhibited strong ADH activation activity. Results suggested that CPH could be a potential nutraceutical for facilitating alcohol metabolism and preventing or ameliorating early liver injury induced by acute alcohol exposure and that the peptide KKLAGFLRYYS is one of the main bioactive components in CPH.