The pathological increase in the levels of reactive oxygen species (ROS) in the retinal pigment epithelium (RPE), is implicated in the development of age-related macular degeneration (AMD). The discovery of drug candidates to effectively protect RPE cells from oxidative damage is required to resolve the pathological aspects and modify the process of AMD. In this study, a FDA-approved anti-malaria drug, Artemisinin was found to suppress hydrogen peroxide (HO)-induced cell death in human RPE cell-D407 cells. Further study showed that Artemisinin significantly suppressed HO induced D407 cell death by restoring abnormal changes in nuclear morphology, intracellular ROS, mitochondrial membrane potential and apoptotic biomarkers. Western blotting analysis showed that Artemisinin was able to activate extracellular regulated ERK/CREB survival signaling. Furthermore, Artemisinin failed to suppress HO-induced cytotoxicity and the increase of caspase 3/7 activity in the presence of the ERK inhibitor PD98059. Taken together, these results suggest that Artemisinin is a potential protectant with the pro-survival effects against HO insult through activation of the ERK/CREB pathway.