Sauchinone, a biologically active lignan isolated from Saururus chinensis, has been reported to show cytoprotective, anti-inflammatory and anti-apoptotic effects. However, little study has been done of the anti-ischemic/hypoxic effect of sauchinone. The present study investigates the anti-ischemic/hypoxic effect of sauchinone by using ischemia/hypoxia-sensitive neuronal cells. We found that sauchinone significantly prevented cortical neurons from oxygen-glucose deprivation (OGD) followed by re-oxygenation. Sauchinone did not inhibit both NMDA-induced cell membrane depolarization and intracellular calcium influx. We further found that sauchinone cannot directly scavenge reactive oxygen and nitrogen species such as H2O2 and peroxynitrite. Sauchinone, however, greatly reduced the formation of reactive oxygen and nitrogen species in neurons exposed to OGD/reoxygenation and inhibited the depolarization of mitochondrial transmembrane potential induced by OGD/reoxygenation. In accordance with diminishment of endogenous ROS production, sauchinone restored the decreased activities of antioxidant enzymes catalase and SOD evoked by OGD/reoxygenation. Specifically, sauchinone up-regulated the activity of catalase, indicating that sauchinone could be a useful cytoprotectant.