<p>Ferroptosis and neuroinflammation are critically involved in the progression of cerebral ischemia/reperfusion (I/R) injury. Fortunellin, a citrus flavonoid, has anti-inflammatory and antioxidant benefits. This research was intended to determine the role of fortunellin in ameliorating cerebral I/R injury, focusing on tis dual effects on ferroptosis and neuroinflammation. Undifferentiated PC12 cells were developed into the <i>in vitro</i> model by exposing to oxygen–glucose deprivation/reperfusion (OGD/R). <i>In vivo</i> model was established in Sprague–Dawley (SD) rats via middle cerebral artery occlusion (MCAO). Fortunellin's influence on cerebral I/R injury was analyzed by using CCK8, ELISA, colorimetry, immunofluorescence, behavioral evaluation (sticker removal test and pole test), TTC staining, H&amp;E staining, TUNEL staining and western blot experiments. The mechanism of fortunellin on cerebral I/R injury involved in NF-κB signaling was explored by immunofluorescence and western blot assays. Treatment with fortunellin enhanced viability in OGD/R-injured PC12 cells and lowered the production of TNF-α, IL-6 and IL-1β. In PC12 cells affected by OGD/R, fortunellin increased GPX4 and SLC7A11 expression and decreased Fe²⁺, ROS, and MDA levels. In rats with MCAO, fortunellin ameliorated brain tissue damage and apoptosis, lowered the Longa neurological scores and minimized the edema and infarct volume. Additionally, fortunellin effectively ameliorated the motor ability of rats. Also, fortunellin lowered TNF-α, IL-6, IL-1β, Fe²⁺, and GPX4 levels. Mechanistically, fortunellin declined the phosphorylation of p65 and IkBα in PC12 cells with OGD/Rand rats following MCAO. Application of RANKL (an activator of NF-κB pathway) reversed the outcomes in the fortunellin-mediated proliferation, ferroptosis and neuroinflammation in PC12 cells. Fortunellin relieved neuroinflammation and ferroptosis in cerebral I/R injury along the modulation of NF-κB axis, identifying a potential drug for its treatment.</p>