LncRNA five prime to Xist (FTX) has been identified to exert a protective effect in multiple diseases. However, whether and how FTX attenuates cerebral ischemia-reperfusion injury (CI/RI) is still unclear. To simulate CI/RI, an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) HT22 cell model and an in vivo middle cerebral artery occlusion/reperfusion (MCAO/R) Sprague-Dawley rat model were respectively constructed. In CI/RI plasma samples, OGD/R-challenged HT22 cells, and brain tissues from MCAO/R rats, FTX and mouse double minute 4 (MDM4) expressions were substantially decreased while miR-186-5p abundance was evidently increased. It was also revealed that FTX obviously improved neuronal damage induced by OGD/R through increasing proliferation, reducing apoptosis, and alleviating oxidative stress in OGD/R-challenged HT22 cells. Additionally, FTX positively regulated MDM4 level in OGD/R-treated HT22 cells as a sponge of miR-186-5p. Moreover, miR-186-5p upregulation or MDM4 suppression restored the inhibitory effects of FTX upregulation on OGD/R-triggered neuronal damage in HT22 cells. Therefore, these results suggest that FTX might ameliorate CI/RI by regulating the miR-186-5p/MDM4 pathway, providing a new target for stroke impairment treatment.