Neurodegenerative disorders are a class of diseases that have been linked to apoptosis induced by elevated levels of reactive oxygen species (ROS). The present study was undertaken to explore the effect of sea cucumber cerebrosides (SCC) and starfish cerebrosides (SFC) on the hydrogen peroxide (H₂O₂) and tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in PC12 cells. Cell viability, the leakage of lactate dehydrogenase (LDH), reactive oxygen species (ROS) level and superoxide dismutase (SOD) activity were determined for their effect on oxidative damage. Quantitative real-time PCR was investigated to analyze the mitochondrial genes expression. These results showed that both SCC and SFC decreased the leakage of LDH and intracellular ROS in a dose-dependent manner. SCC and SFC could also increase the SOD activity compared with the model groups. In H₂O₂ damage model, 400 μg/mL SCC increased the SOD activity by 79%, which was stronger than SFC. The results demonstrated that SCC and SFC exhibited the protective effects, which may be related to their antioxidant action. In addition, SCC and SFC dramatically increased the gene expression of B-cell lymphoma 2 (Bcl-2) but significantly decreased the gene expression of Cytochrome c, caspase9 and caspase3 compared with H₂O₂ or t-BHP treatment. These results suggested that SCC and SFC might exert a protective function against oxidative damage by inhibiting mitochondria-mediated apoptosis pathway. In conclusion, SCC and SFC played an important protective role in H₂O₂ and t-BHP-induced damage of PC12 cells, suggesting that the SCC and SFC may be a potential therapeutic agent against nervous system oxidative damage.