Nitric oxide (NO) is an important neurotransmitter and neuromodulator that responds to various stimuli. However, excessive NO levels constitute one of the main causes of retinal pigment epithelium (RPE) cells degeneration leading to the onset of several eye diseases, such like Age-Related Macular Degeneration (AMD). Nerve growth factor (NGF), an important neurotrophic factor, is mainly involved in the survival, proliferation and functional maintenance of nerve cells. This study aimed to assess the protective effect of NGF in human RPE cells D407 against sodium nitroprusside (SNP) induced injury and the underlying mechanisms. SNP reduced the survival of D407 cells in a concentration dependent manner and NGF pretreatment significantly suppressed SNP-induced injury as shown by the decrease of intracellular reactive oxygen species (ROS) accumulation, the prevention of mitochondrial membrane potential (ΔΨm) decline and the reduction of apoptosis. Assessment of the underlying mechanisms revealed that NGF stimulated the activation of PI3K/Akt and Erk1/2 signaling pathways. Upon inhibition of PI3K/Akt and Erk1/2 pathways (LY294002 and PD98059, respectively) the protective effect of NGF in D407 cells was blocked. These data suggest that NGF protects RPE cells from NO-induced injury via activation of cell survival cascades associated to PI3K/Akt and Erk1/2 signaling pathways.