Hypoxic-ischemic brain damage (HIBD) is a major contributor to neurological disabilities. Our previous studies have demonstrated that DL-3-n-butylphthalide (NBP) confers protective effects against HIBD and mitigates blood-brain barrier (BBB) impairment, but the underlying mechanism remains unclear. This study aimed to investigate the mechanism by which NBP protects against ferroptosis-induced BBB damage. Our results showed that NBP treatment significantly reduced infarct volume (by 24.09%), alleviated cerebral edema (brain water content decreased by 1.651%), attenuated BBB disruption, suppressed neuroinflammation, promoted neuronal repair, and improved functional recovery. Using RNA sequencing, molecular docking, and surface plasmon resonance (SPR) assays, we discovered for the first time that NBP directly binds to membrane-bound SLC7A11 with a KD value of 222.0 µM, thereby activating the SLC7A11/GSH/GPX4 pathway and inhibiting ferroptosis in cerebrovascular endothelial cells. Different from previously reported anti-apoptotic and anti-inflammatory mechanisms of NBP, the present study reveals a novel mechanism by which NBP protects the BBB through inhibiting endothelial ferroptosis. The protective effect of NBP was further validated by knocking down SLC7A11 with specific siRNA, confirming its dependence on SLC7A11. Ultimately, NBP ameliorated BBB damage both in vitro and in vivo. In summary, NBP attenuates BBB disruption by targeting the SLC7A11/GSH/GPX4 pathway and inhibiting endothelial ferroptosis, thereby reducing brain injury and promoting neural recovery.