INTRODUCTION: αAsarone, an essential oil derived from METHODS: The effects of αAsarone on autophagy were examined by WB, RT-qPCR, immunofluorescence colocalization, transmission electron microscope, and autophagic flux activity was measured by infecting HT22 cells with mRFP-GFP-LC3 adenovirus. And then, cells were transfected with both mimic-miR-499-5p and inhibit-miR-499-5p to investigate the role of miR-499-5p in regulating the effects of αAsarone on stroke. To further clarify the protective effect of αAsarone RESULTS: αAsarone was observed to inhibit the apoptosis of neuronal cells, and enhance autophagy. In addition, αAsarone promoted the expression of miR-499-5p. Targeting miR-499-5p can negatively regulate PDCD4 expression and the results from the dual-luciferase reporter assay demonstrate the direct targeting of PDCD4 by miR-499-5p. Promoting miR-499-5p can decrease the expression of PDCD4, increase ATG5, and enhance the protective effect of αAsarone on OGD/R injury while inhibiting miR-499-5p can weaken the effect of αAsarone. DISCUSSION: Our data suggest that αAsarone alleviates neuronal injury of stroke by facilitating neuronal autophagy through the miR-499-5p/PDCD4/ATG5 signaling pathway.