Blood–brain barrier (BBB) disruption is a major pathophysiological event of is-chemic stroke. Brain microvascular endothelial cells are critical to maintain homeo-stasis between central nervous system and periphery. Resveratrol protects againstischemic stroke. 3,3′,4,5′-tetramethoxy-trans-stilbene (3,3′,4,5′-TMS) and 3,4′,5- trimethoxy-trans-stilbene (3,4′,5-TMS) are resveratrol derivatives with addition ofmethoxy groups, showing better pharmacokinetic performance. We aimed to ex-plore their protective effects and underlying mechanisms. Oxygen–glucose dep-rivation (OGD) model was applied in bEnd.3 cell line, mouse brain microvascularendothelium to mimic ischemia. The cells were pre-treated with 3,3′,4,5′- TMS or3,4′,5-TMS (1 and 5 μM, 24 h) and then subjected to 2-h OGD injury. Cell viabil-ity, levels of proinflammatory cytokines and reactive oxygen species (ROS), andprotein expressions were measured by molecular assays and fluorescence stain-ing. OGD injury triggered cell death, inflammatory responses, ROS productionand nuclear factor-kappa B (NF-κB) signalling pathway. These impairments wereremarkably attenuated by the two stilbenes, 3,3′,4,5′-TMS and 3,4′,5-TMS. Theyalso alleviated endothelial barrier injuries through upregulating the expression oftight junction proteins. Moreover, 3,3′,4,5′-TMS and 3,4′,5-TMS activated 5′ adeno-sine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxidesynthase (eNOS). Overall, 3,3′,4,5′-TMS and 3,4′,5-TMS exert protective effectsagainst OGD damage through suppressing cell death, inflammatory responses, oxi-dative stress, as well as BBB disruption on bEnd.3 cells.