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Neutrophil infiltration and phenotypic transformation are believed to contribute to neuronal damage in ischemic stroke. Emerging evidence suggests that histone deacetylase 2 (HDAC2) is an epigenetic regulator of inflammatory cells. Here, we aimed to investigate whether microRNA‐494 (miR‐494) affects HDAC2‐mediated neutrophil infiltration and phenotypic shift. MiR‐494 levels in neutrophils from acute ischemic stroke (AIS) patients were detected by real‐time PCR. Chromatin Immunoprecipitation (ChIP)‐Seq was performed to clarify which genes are the binding targets of HDAC2. Endothelial cells and cortical neurons were subjected to oxygen‐glucose deprivation (OGD), transwell assay was conducted to examine neutrophil migration through endothelial cells, and neuronal injury was examined after stimulating with supernatant from antagomiR‐494‐treated neutrophils. C57BL/6J mice were subjected to transient middle cerebral artery occlusion (MCAO) and antagomiR‐494 was injected through tail vein immediately after reperfusion, and neutrophil infiltration and phenotypic shift was examined. We found that the expression of miR‐494 in neutrophils was significantly increased in AIS patients. HDAC2 targeted multiple matrix metalloproteinases (MMPs) and Fc‐gamma receptor III (CD16) genes in neutrophils of AIS patients. Furthermore, antagomiR‐494 repressed expression of multiple MMPs genes, including MMP7, MMP10, MMP13, and MMP16, which reduced the number of brain‐infiltrating neutrophils by regulating HDAC2. AntagomiR‐494 could also exert its neuroprotective role through inhibiting the shift of neutrophils toward pro‐inflammatory N1 phenotype in vivo and in vitro. Taken together, miR‐494 may serve as an alternative predictive biomarker of the outcome of AIS patients, and antagomiR‐494 treatment decreases the expression of multiple MMPs and the infiltration of neutrophils and inhibits the shift of neutrophils into N1 phenotype partly by targeting HDAC2. [ABSTRACT FROM AUTHOR]