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&NA; Luteoloside, a flavonoid compound, has been reported to have anti‐inflammatory, anti‐oxidative, antibacterial, antiviral, anticancer, and cardioprotective effects, among others, but its neuroprotective effects have rarely been studied. The purpose of this study was to investigate the protective effect of luteoloside on cerebral ischemia and explore its potential mechanism. Middle cerebral artery occlusion (MCAO) was performed to investigate the effects of luteoloside on cerebral ischemia‐reperfusion (I/R). Male Sprague‐Dawley rats were randomly divided into six groups: sham, MCAO, luteoloside (20 mg/kg, 40 mg/kg, 80 mg/kg) and nimodipine (4 mg/kg). The results showed that luteoloside alleviated neurologic deficits and cerebral edema as well as improved cerebral infarction and histopathological changes in MCAO rats. Luteoloside significantly inhibited I/R‐induced neuroinflammation, as demonstrated by reduced levels of interleukin‐1&bgr; (IL‐1&bgr;), tumor necrosis factor‐&agr; (TNF‐&agr;), inducible nitric oxide synthase (iNOS) and cyclooxygenase‐2 (COX‐2) in the brain tissues of MCAO rats. Furthermore, our results demonstrated that luteoloside significantly suppressed the activation of nuclear factor‐kappa B (NF‐&kgr;B) signaling, upregulated the protein expression of peroxisome proliferator activated receptor gamma (PPAR&ggr;) and increased NF‐E2‐related factor (Nrf2) nuclear accumulation in MCAO rats. Collectively, our findings suggested that luteoloside played a crucial neuroprotective role by inhibiting NF‐&kgr;B signaling in focal cerebral ischemia in rats. Furthermore, PPAR&ggr; and Nrf2 were also important for the anti‐inflammatory effect of luteoloside. In addition, our data suggested that luteoloside might be an effective treatment for cerebral ischemia and other neurological disorders. Graphical abstract Figure. No caption available. HighlightsLuteoloside exerted a protective effect on cerebral ischemic injury induced by MCAO in ratsLuteoloside played an anti‐inflammatory role in cerebral ischemic process by suppressing NF‐&kgr;B signaling pathways.Luteoloside could up‐regulated the PPAR&ggr; expression and activited the Nrf2 signaling to attenuate cerebral ischemic injury.