Objective: To investigate the effect and mechanism of resveratrol on neural cell apoptosis induced by endoplasmic reticulum stress (ERS). Methods: PC12 cells were treated with ERS inducer thapsigargin (TG) to construct ERS model. The expression of GRP 78 protein was detected by Western blotting, the cytoplasmic calcium concentration ([Ca2+]i) was detected by laser scanning confocal microscope (LSCM) and fluo-3, the activity of Caspase-3 was measured by colorimetry, and the apoptosis rate was detected by flow cytometry. Results: (1)Resveratrol reduced the high expression of GRP 78 induced by ERS inducer TG; (2)Resveratrol prevented calcium overload induced by ERS; (3)Resveratrol and calcium chelator BAPTA inhibited the activation of Caspase-3 induced by ERS; (4)Resveratrol and calcium chelator BAPTA inhibited ERS-induced neuronal apoptosis. Conclusion: Resveratrol might inhibit neural cell apoptosis induced by ERS through Ca2+/caspase-3 pathway.