Parthenolide (PN), a sesquiterpene lactone isolated from the herbal medicine feverfew (Tanacetum parthenium), was reported to possess neuroprotective activity. However, the neuroprotective effect of PN against cerebral ischemia/reperfusion (I/R) injury remains unclear. Therefore, the aim of the present study was to explore the neuroprotective effects of PN against oxygen-glucose deprivation (OGD)-induced apoptosis in PC12 cells and the underlying mechanisms. Our results demonstrated that PN ameliorated OGD/R-evoked neuronal injury and oxidative stress in PC12 cells. In addition, PN notably decreased HIF-1α expression, as well as inhibited apoptosis in PC12 cells after OGD/R. Furthermore, PN pretreatment significantly enhanced the phosphorylation of Akt and GSK-3β in PC12 cells exposed to OGD/R. In conclusion, the present study demonstrated that PN exhibits a neuroprotective effect against OGD/R through activation of the Akt/GSK-3β signaling pathway. Our findings suggest that PN has the potential to serve as a novel therapeutic agent for cerebral I/R injury.