Quercetin (3,3,4,5,7-Pentahydroxyflavone, Qu) is a promising cancer chemo-preventive agent for various cancers because it inhibits disease progression and promotes apoptotic cell death.In our previous study, we demonstrated that Qu could evoke ER stress to enhance drug cytotoxicity in ovarian cancer.However, Qu-induced ER stress in ovarian cancer is still poorly understood.Here, we demonstrated that Qu evoked ER stress to involve in mitochondria apoptosis pathway via the p-STAT3/Bcl-2 axis in ovarian cancer cell lines and in primary ovarian cancer cells.Unexpectedly,inhibition of ER stress did not reverse Qu-induced cell death.Further functional studies revealed that Qu-induced ER stress could activate protective autophagy concomitantly by activating the p-STAT3/Bcl-2 axis in this process.Moreover, the autophagy scavenger 3-MA was shown to enhance Qus anticancer effects in an ovarian cancer mice xenograft model.These findings revealed a novel role of ER stress as a "double edge sword" participating in Qu-induced apoptosis of ovarian cancer and might provide a new angle to consider in clinical studies of biological modifiers that may circumvent drug resistance in patients by targeting protective autophagy pathways.