The purpose of this study was to investigate the cytoprotective effects of a neutrase enzymatic hydrolysate derived from Buccinum striatissumum (BSMN) against hydrogen peroxide (H2O2)-induced oxidative damage in hepatocytes. BSMN effectively scavenged the 2,2-azino-bis (3-ethylbenzthiazoline)-6-sulfonic acid radical (ABTS) and increased the oxygen radical absorbance capacity (ORAC) value by incresing the reducing power. Also, BSMN markedly increased the cell viabiltiy by inhibiting the intracellualr reactive oxygen species (ROS) production in H2O2-stimulated hepatocytes. In addition, BSMN decreased the sub-G1 DNA contents and apoptotic body formation increased by regulating the apoptosis related proteins (Bcl-2, Bax and p53). Moreover, BSMN activated the Nrf2/HO-1 signaling pathway by suppressing the activation of NF-κB and ERK/p38 signaling in H2O2-stimulated hepatocytes. These results suggest BSMN protects hepatocytes against oxidative stress caused by H2O2 stimulation