We previously found that ginsenoside Rd (GSRd), one of the main active ingredients in Panax Ginseng, attenuates H(2)O(2)-induced oxidative injury in PC12 cells. Mounting evidence suggests that the oxidative stress is crucially involved in the pathophysiologic process of ischemia. In the present study, we examined the protective role of GSRd to attenuate ischemic neuronal injury in vitro. Cultured hippocampal neurons were exposed to oxygen-glucose deprivation (OGD) for 2h followed by a 24-h reoxygenation. GSRd exhibited remarkable neuroprotection when presented during OGD and reoxygenation, which may be ascribed to its antioxidative properties by reducing the intracellular reactive oxygen species and malondialdehyde production; increasing glutathione content; and enhancing the antioxidant enzymatic activities of catalase, superoxide dismutase and glutathione peroxidase. Additionally, GSRd could stabilize the mitochondrial membrane potential and attenuate apoptotic death of hippocampal neurons after OGD exposure. These findings suggested that GSRd may be a potential neuroprotective agent for cerebral ischemic injury and should encourage further in vivo studies on stroke to explore the potential neuroprotective efficacy of GSRd.