MicroRNAs (miRNAs) have emerged as novel regulators in various pathological processes including ischemic stroke. However, the precise role of miRNAs in ischemic stroke remains largely unknown. In this study, we investigated the role of miR-137 in the regulation of neuronal ischemia/reperfusion injury with oxygen-glucose deprivation and reoxygenation (OGD/R), a model of global brain ischemia. The results showed that miR-137 was significantly downregulated in neurons subjected to OGD/R treatment: OGD/R-induced cell injury was markedly inhibited by miR-137 overexpression and exacerbated by miR-137 suppression. Moreover, Notch1 was predicted as a target gene of miR-137 and verified by dual-luciferase reporter assay, real-time quantitative polymerase chain reaction, and western blot analysis. Through targeting of Notch1, miR-137 regulated the Notch signaling pathway. The blockade of the Notch signaling pathway reversed the effect of miR-137 suppression, whereas overexpression of the Notch intracellular domain abrogated the effect of miR-137 overexpression on OGD/R-induced cell injury. Overall, our study suggests that miR-137 regulated the Notch signaling pathway by targeting Notch1 to protect neurons from OGD/R-induced cell injury, providing a novel insight into understanding the molecular basis of ischemia stroke and a potential therapeutic target.