Though electrical stimulation is used as a therapeutic approach to treat retinal and spinalinjuries, many protective mechanisms at cellular level have not been elucidated. We performeda detailed analysis of cellular events in blue light (Li) stressed 661W cells, which were subjectedto direct current electric field (EF) stimulation. Our findings revealed that EF stimulation inducedprotective effects in 661W cells from Li-induced stress by multiple defense mechanisms, such asincrease in mitochondrial activity, gain in mitochondrial potential, increase in superoxide levels, andthe activation of unfolded protein response (UPR) pathways, all leading to an enhanced cell viabilityand decreased DNA damage. Here, our genetic screen results revealed the UPR pathway to be apromising target to ameliorate Li-induced stress by EF stimulation. Thus, our study is important fora knowledgeable transfer of EF stimulation into clinical application.