Ischemic stroke, a severe cerebrovascular disease, is particularly prevalent among the elderly. Rsearch has indicated that histone deacetylases (HDACs) are pivotal in the pathogenesis of ischemic stroke. We introduce a novel HDACs inhibitor, HDI-1, as a potential therapeutic strategy for this condition. Our study reveals that HDI-1 expedites the restoration of tight junction proteins, Occludin and Claudin-5, in the oxygen-glucose deprivation/reoxygenation (OGD/R) model using human cerebral microvascular endothelial cells (hCMEC/D3). Moreover, HDI-1 mitigates the impairment of cellular monolayer membrane permeability following injury. This effect may stem from HDI-1's ability to selectively suppress the enzymatic activity of HDAC2. By inhibiting the activation of the NF-κB pathway triggered by OGD/R injury, HDI-1 reduces the secretion of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, thereby diminishing the inflammatory response in hCMEC/D3 cells. Meanwhile, HDI-1 exhibits antioxidant properties by enhancing the Nrf2/HO-1 signaling pathway. Collectively, our findings propose HDI-1 as a promising candidate for ischemic stroke treatment.