Blood-brain barrier (BBB) damage and dysfunction are critical pathological features associated with cerebral ischemia-reperfusion injury in stroke. Fenofibrate, a lipid-regulating drug, has an unclear role in BBB function during stroke. This study investigates the effects of fenofibrate on BBB disruption and cerebrovascular endothelial cells induced by ischemia-reperfusion. Cerebral ischemia-reperfusion injury (CIRI) models were established using the middle cerebral artery occlusion (MCAO) method. Blood-brain barrier (BBB) integrity was assessed using Evans blue dye. The permeability of human brain microvascular endothelial cells (HBMVECs) was evaluated using fluorescein isothiocyanate (FITC)-dextran permeation assays and trans-endothelial electrical resistance (TEER) measurements. Additionally, real-time polymerase chain reaction (PCR), immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and Western blot analysis were performed. We found that the administration of fenofibrate improved brain endothelial dysfunction by reducing the expression of vascular cell adhesion molecule- 1 (VCAM- 1) and E-selectin in MCAO mice. Furthermore, fenofibrate restored the expression of the tight junction protein occludin in the cortices of MCAO mice. Notably, fenofibrate alleviated BBB dysfunction in MCAO mice. In vitro studies demonstrated that fenofibrate ameliorated endothelial monolayer permeability under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions and inhibited the expression of VCAM- 1 and E-selectin in HBMVECs. Moreover, fenofibrate restored occludin expression following OGD/R. We identified a novel mechanism whereby fenofibrate suppressed the elevation of Egr- 1 induced by OGD/R; however, overexpression of Egr- 1 abrogated the protective effects of fenofibrate on the upregulation of VCAM- 1 and E-selectin and the downregulation of occludin induced by OGD/R. Furthermore, overexpression of early growth response- 1 (Egr- 1) negated the protective effects of fenofibrate on endothelial monolayer permeability and trans-endothelial electrical resistance (TEER). Our findings suggest that fenofibrate may be a promising therapeutic agent for stroke treatment.