The present study is designed to investigate the neuroprotective effect of a kind of phlorotannins, diphlorethohydroxycarmalol (DPHC) isolated from Ishige okamurae against hydrogen peroxide (H2O2)-induced oxidative stress in murine hippocampal neuronal cells, HT22. H2O2 treatment induced neurotoxicity, whereas DPHC prevented cells from H2O2-induced damage then restoring cell viability was significantly increased. DPHC slightly reduced the expression of Bax induced by H2O2 but recovered the expression of Bcl-xL as well as caspase-9 and -3 mediated PARP cleavage by H2O2. Intracellular reactive oxygen species (ROS) and lipid peroxidation was overproduced as the result of the addition of H2O2; however, these ROS generations and lipid peroxidation were effectively inhibited by addition of DPHC in a dose-dependent manner. Moreover, DPHC suppressed the elevation of H2O2-induced Ca2+ release. These findings indicate that DPHC has neuroprotective effects against H2O2-induced damage in neuronal cells, and that an inhibitory effect on ROS production may contribute to the underlying mechanisms.