AbstractThe modulatory mechanism of flurbiprofen axetil (FPA) by which it relieves cerebral ischemia/reperfusion (I/R) injury (CIRI) is still obscure. In the present work, adult male Sprague‐Dawley (SD) rats were pre‐treated with FPA before the construction of a rat model of CIRI. Longa's scoring method and dry–wet method were employed to examine the neurological function and brain water content of the rats. MiR‐30c‐5p, SOX9, AQP4, SOX9, NF‐κB, and p‐NF‐κB expression levels in the brain tissues of the rats were examined by qRT‐PCR or Western blot. ELISA was executed to evaluate the IL‐10, IL‐6, and TNF‐α levels in the serum of rat. SOD and MDA levels in rat brain homogenates were also examined to indicate the oxidative stress. Hematoxylin‐eosin (HE) staining was used to examine the pathological changes of the brain tissues. Dual‐luciferase reporter gene experiment was implemented to validate the binding relationship between miR‐30c‐5p and SOX9. In the present work, compared with the rats with CIRI, FPA pre‐treatment attenuated neurological injury, cerebral edema, oxidative stress, inflammatory response, and cerebral pathological changes in the rat model with CIRI. FPA up‐modulated miR‐30c‐5p expression. SOX9 was a downstream target of miR‐30c‐5p. In conclusion, FPA ameliorates CIRI through up‐modulating miR‐30c‐5p expression and reducing SOX9 expression.