Temporal post-conditioning to induce neuroprotection against brain ischemia-reperfusion injury insult is considered to be an effective intervention, but the exact mechanisms of sevoflurane post-conditioning are poorly understood. Extracellular signal-related kinases 1/2 (Erk1/2) play a pivotal role in the cell growth and proliferation. The essential axis of activator Bid, Bim, Puma (BH3s) and BAX, BAK in activating the mitochondrial death program might offer common ground for cell death signal. We hypothesized that, sevoflurane post-conditioning might inhibit the expression of Bid, Bim and Puma and is activated by phosphor-Erk1/2 to reduce neuronal death. To test this hypothesis, we exposed primary cultured cortical neurons to oxygen-glucose deprivation for 1 h and resuscitation for 24 h (OGD/R). The assays of MTT, propidium iodide uptake, JC-1 fluorescence and western blot demonstrated that OGD/R exposure reduced cell viability, increased cell death, decreased mitochondrial membrane potential and the expressions of Bid, Bim, and Puma. Inhibition of Erk1/2 phosphorylation could partially attenuate 2 % of sevoflurane post-conditioning mediated increase in neuronal viability and mitochondrial membrane potential, and also a decrease in cell death and expression of Bid, Bim and Puma after OGD/R treatment. The results demonstrated that, the protection of sevoflurane post-conditioning markedly reducing death of cortical neurons exposed to OGD/R could be correlated with down-regulation of Bid, Bim and Puma expression mediated by phosphorylation/activation of Erk1/2.