Abstract: Nitric oxide (NO) is a crucial neurotransmitter and neuromodulator in response to various stimuli. However, excess NO is one of the important causes of degeneration of Retinal pigment epithelium (RPE) cells which leads to the development of Age-Related Macular Degeneration (AMD). In the present study, we studied the protective effects of the nerve growth factor (NGF) on D407 cells, a human RPE cell line, against sodium nitroprusside (SNP, a nitric oxide donor) induced injury and its underlying mechanism. MTT assay showed that SNP concentration-dependently caused the death of D407 cells while the pretreatment of D407 cells with NGF significantly suppressed SNP-induced injury to D407 cells. Moreover, NGF attenuated the accumulation of intracellular reactive oxygen species (ROS), prevented the decline of mitochondrial membrane potential and reduced the apoptosis of D407 cells exposed to SNP. Western blot analysis revealed that NGF stimulated the activation of the MAPK and PI3K/Akt signaling pathways while the PI3K inhibitor LY294002 and MAPK pathway inhibitor PD98059 blocked the protective effects of NGF. Moreover, we found the FoxO3a was also phosphorylated in the protective action of NGF on D407 cells. These data put together suggested that NGF can protect RPE cells from NO-induced injury via the activation of the PI3K/Akt/FoxO3a and MAPK pathways.