Nobiletin (NOB) possesses multiple pharmacological effects, but its anti-apoptotic property has acquired a great deal of attention. Endoplasmic reticulum (ER) stress (ERS)-induced apoptosis acts as the pivotal aetiology in neuronal oxygen-glucose deprivation and reoxygenation (OGD/R) injury. The aim of this study focused on whether NOB exerts neuro-protective effects on OGD/R injury by repressing ERS-induced apoptosis. The PC12 neuronal cell line was subjected to 4 h OGD and 24 h reoxygenation following NOB treatment. A PI3K/AKT inhibitor (LY294002) was added during the mechanistic experiments. Cell viability, lactate dehydrogenase (LDH) release and apoptosis were determined. Western blotting was used to measure protein expression levels. The results showed that OGD/R caused neuronal damageas exhibited by the increase in LDH release and the reduction of cellular viability. Moreover, ERS-induced apoptosis was markedly stimulated by OGD/R in PC12 cells, as evidenced by the elevation in the apoptotic rate and protein levels of C/EBP homologous protein/glucose-regulated protein-78. However, NOB administration significantly reversed neuronal damage and the ERS-induced apoptosis in response to OGD/R injury. Mechanistic detections showed that the neuron-favorable and ERS-repressing contributions of NOB were, in part, a result of the activation of the PI3K/AKT pathway, which was validated by a specific PI3K/AKT inhibitor (LY294002). Therefore, NOB protects PC12 cells from ERS-induced apoptosis in OGD/R injury mainly through enhancement of the PI3K/AKT pathway, which may provide a novel therapeutic avenue for the prevention of cerebral ischemia/reperfusion injury.