The accumulation of damage caused by oxidative stress exacerbates cell death in many neurodegenerative diseases. We evaluated the mechanism of neuronal cell death raised by glutamate-induced toxicity, using the immortalized mouse hippocampal cell line HT-22. Our results showed that vitamin E prevented glutamate-induced cell death, accompanied by the decline of cyclooxygenase-2 expression confirmed by reverse transcriptase polymerase chain reaction and immunocytochemistry. Moreover, the neuroprotection was still effective even when vitamin E was supplied after glutamate treatment. The decline of cyclooxygenase-2 activity was also highly correlated with the neural protective effect against glutamate-induced toxicity. These results represent new insights about the timing of vitamin E supplementation after toxic stimulation and one mechanism by which vitamin E could prevent neuronal cell death by controlling cyclooxygenase-2 activity.