Hypertonic saline (HS) attenuates cerebral edema, improves microcirculation perfusion and alleviates inflammation. However, whether the beneficial effect of HS on neurological function after cardiopulmonary resuscitation (CPR) in rat model of asphyxial cardiac arrest (CA) is mediated via attenuating apoptosis of neurons is not known. We studied the neuroprotective effect of HS in rats after CA and CPR, and explored the likely underlying mechanisms. Animals were randomly assigned to 4 equal groups (n = 15 each) according to the different infusions administered during resuscitation: control (C), normal saline (NS), hypertonic saline (HS), and hydroxyethyl starch (HES) groups. NDS at 12, 24, 48 and 72 h post-ROSC in the HS group were significantly higher than those in the NS and HES groups. Western blot analysis demonstrated a significant increase in Bcl-2 expression in HS, as compared to that in the NS and HES groups. However, Bax and Caspase-3 expressions in HS were significantly lower than that in the NS and HES groups. The apoptosis rate in HS was significantly lower than that in the NS and HES groups, suggesting HS treatment during resuscitation could effectively suppress neuronal cell apoptosis in hippocampal CA1 post-ROSC and improve neuronal function.