Salidroside exhibits anti-inflammatory, anti-oxidative, and anti-apoptotic properties. To identify whether salidroside might be a candidate for treating ischemic stroke, we investigated the effects of salidroside or vehicle, given daily for 6 days, after middle cerebral artery occlusion (MCAO) for 2 h and reperfusion for either 1 or 48 h in rats. Salidroside reduced cerebral infarct volume and significantly improved neurological scores whether started after 1 or 48 h of reperfusion. Microarray analysis showed that 20 % (133/678) of the genes down-regulated by ischemia and 1 h of reperfusion were up-regulated by salidroside, whereas 13 % (105/829) of the genes induced by ischemia-reperfusion were inhibited by salidroside, suggesting that salidroside can reverse effects of ischemia-reperfusion on gene expression. The main enriched functional categories induced by salidroside were genes related to synaptic plasticity, whereas salidroside inhibited genes related to inflammation. Induction of Egr1, Egr2, Egr4, and Arc by salidroside was confirmed by qRT-PCR and western blotting in ischemic brains treated after either 1 or 48 h of reperfusion. The potential protective role of Egr4 in salidroside-mediated neuroprotection was subsequently investigated in CoCl2-treated PC12 cells. Egr4 was dose-dependently induced by salidroside in PC12 cells, and depleting Egr4 with target-specific siRNA increased caspase-3 activity and Bax, but decreased Bcl-xl, which were reversed by salidroside. Finally, we confirmed that salidroside inhibited the Bax/Bcl-xl-related apoptosis after MCAO with reperfusion. In conclusion, salidroside is highly neuroprotective with a wide therapeutic time window after ischemia-reperfusion injury in the rat, and this partially involves induction of Egrs, leading to inhibition of Bax/Bcl-xl-related apoptosis.