Homosyringaldehyde was isolated and identified from the 80% methanol extract of roots of Cynanchum paniculatum. C. paniculatum has been widely used for the treatment of various diseases such as neurasthenia, insomnia, dysmenorrheal and toothache. This compound exerted significant neuroprotective activities against glutamate-induced neurotoxicity in hippocampal HT22 cell line by 37.53% (at the concentration of $100{mu}M$). We investigated mode of action of this compound. Homosyringaldehyde ($100{mu}M$) significantly decreased the ROS level and $Ca^{2+}$ concentration in the oxidative stress induced HT22 cells by oxidative glutamate toxicity. Thus, our results suggest that homosyringaldehyde significantly protect HT22 cells against glutamate-induced oxidative stress, via antioxidative activities. As the results, we suggest that homosyringaldehyde may be useful in the treatment of neurogenerative disorders.