Our previous studies have showed that ginsenoside (GS)-Rd, a mono-compound isolated from traditional Chinese herb panax ginseng, has the neuroprotective effects following ischemic stroke. However, the underlying mechanisms are still largely unknown. Our latest study showed that GS-Rd could block calcium influx in cultured cortical neurons after excitotoxic injury, indicating that GS-Rd may act on cation channels. To explore this possibility, in this study, we used a rat middle cerebral artery occlusion (MCAO) model to examine the effects of GS-Rd on the expression of non-selective cation channels, including transient receptor potential melastatin (TRPM) and acid sensing ion channels (ASIC), and cation channels, including N-methyl-D-aspartate (NMDA) receptors, which all play essential roles in ischemic stroke. Our results showed that both TRPM and ASIC channels were expressed in the brain. At 24 h following MCAO insult, mRNA and protein expression levels of TRPM7, ASIC1a and ASIC2a were significantly increased. Pretreatment of 10 mg/kg GS-Rd attenuated MCAO-induced expression of TRPM7 and ASIC1a but promoted that of ASIC2a. In contrast, GS-Rd had no significant effects on the expression of NMDA receptors. Thus, our results suggest that GS-Rd neuroprotection following cerebral ischemia may be at least due to its effects on the expression of TRPM7, ASIC1a and ASIC2a.