This study aimed to explore whether USP18 regulates cerebral ischemia-reperfusion (I/R) injury via fat mass and obesity-associated proteins (FTO)-mediated NCOA4. Middle cerebral artery occlusion (MCAO) models were established in mice, and PC-12 cells treated with oxygen-glucose deprivation and reperfusion (OGD/R) were used as in vitro models. The USP18 lentiviral vector was transfected into cells in vitro and MCAO mice to observe its effect on ferroptosis. The relationship between USP18 and FTO was assessed using Co-IP and western blot. The effect of FTO on NCOA4 m6A modification was also elucidated. Overexpression of USP18 in MCAO models decreased cerebral infarct size and attenuated pathological conditions in mouse brain tissues. Moreover, USP18 reduced iron content, MDA, ROS, and LDH release, increased GSH levels and cell viability in both MCAO models and OGD/R cells, and promoted LC3 expression and autophagy flux. In vitro experiments on neurons showed that USP18 maintained FTO stability. The presence of FTO-m6A-YTFDH1-NCOA4 was also verified in neurons. Both in vivo and in vitro experiments showed that FTO and NCOA4 abrogated the protective effects of USP18 against ferritinophagy-mediated ferroptosis. Notably, USP18 maintains FTO stability, contributing to the removal of NCOA4 m6A modification and the suppression of NCOA4 translation, which consequently inhibits ferritinophagy-mediated ferroptosis to attenuate cerebral I/R injury.