Objective: We investigated whether Piezol could regulate oxygen-glucose deprivation/reoxygenation injury of neurons through Ca2+/calpain signaling. Methods: Piezol expression in rat brain cortex and PC12 cells were confirmed by immunohistochemistry, immunofluorescence and Western blotting. The effects of Yodal and GsMTx4 on OGD/R-induced decrease in cell viability, increase in cell apoptosis and activation of downstreaming Ca2+/calpain signaling were investigated. Furthermore, calpain signaling was inhibited by PD151746 to see whether Ca2+/calpain signaling participated in the neurotoxic effects of Piezol activation. Results: Piezol expression was increased in rat cerebral cortex after ischemia/reperfusion and in PC12 cells after OGD/R. Activation of Piezol by Yodal enhanced OGD/R-induced cell viability inhibition, apoptosis, increase intracellular calcium levels and enhanced calpain activity while GsMTx4 showed the opposite effects. The effects of Piezol activation on cell viability and apoptosis were reversed by PD151746. Conclusion: Piezol could regulate neuron oxygen-glucose deprivation/reoxygenation injury via activation of Ca2+/calpain signaling. (C) 2019 Published by Elsevier Inc.