Objective To investigate the neuroprotective effect of ibuprofen on ischemic stroke （IS） rats by regulating nuclear factor E2-related factor 2（Nrf2）/non-glycosylated xCT （SLC7A11）/glutathione peroxidase 4 （GPX4） signaling pathway. Methods Forty eight IS rats prepared under the middle cerebral artery infarction model were randomly divided into IS group， treatment group （30 mg/kg ibuprofen）， inhibitor group （30 mg/kg ML385）， and treatment + inhibitor group （30 mg/kg ibuprofen + 30 mg/kg ML385）. Another 12 rats were set as a sham-operated group， where the rats were prepared only by separating the blood vessels instead of ligating them. After intervention， the neurological function of the rats was scored， and the rate of cerebral infarction and the content of cerebral edema were detected. After that， the rat brain tissue was removed to observe the morphological changes of neurons，measure the contents of iron ion and detect the expression of proteins related to the Nrf2/ SLC7A11/GPX4 signaling pathway. Results Compared with the sham operation group， the neurological function score， cerebral infarction rate， cerebral edema content and iron ion content in IS group were significantly increased， and the expressions of Nrf2， SLC7A11 and GPX4 were obviously decreased （P < 0.05）； compared with the IS group， the neurological function score， cerebral infarction rate， cerebral edema content and iron ion content in the treatment group were obviously decreased， and the expressions of Nrf2， SLC7A11， and GPX4 were significantly increased as well. The neuroprotection of the treatment group on IS rats was reversed in the inhibitor group. Conclusion Ibuprofen can protect nerve damage in IS rats， which may be related to the activation of Nrf2/ SLC7A11/GPX4 signaling pathway.