Melatonin plays a neuroprotective role in different CNS injuries. However, the molecular mechanisms underlying neuroprotection by melatonin are not well understood. Here, we studied the effects of melatonin in hypoxia-induced N2a cells and our results demonstrated that melatonin not only reduced the level of ROS and MDA, induced the increase of SOD, but also increased the cell proliferation and inhibited cell apoptosis in hypoxia-induced N2a cells. Moreover, we identified that melatonin can activate the MAPK/ERK pathway via upregulating the expression of Zip1. Therefore, this study provides a new mechanism of melatonin and need our further study in detail.