Prolonged ischemia can result in apoptotic death of vascular endothelial cells and lead to ischemic vascular diseases including vascular dementia, arteriosclerosis and brain oedema. Finding protective strategies to prevent this is therefore an urgent mission. Recent studies have shown that dysregulation of microRNAs (miRNAs) can lead to imbalance of Bcl-2 family proteins and mitochondrial dysfunction, leading to further damage of vascular cells under ischemic conditions. However, whether miRNAs can be used as a drug target for treating vascular diseases is not fully understood. In this study, we observed that the natural product 2,4,5-trihydroxybenzaldehyde (TDB) could effectively inhibit vascular cell apoptosis following oxygen-glucose deprivation/reperfusion (OGD/R) by maintaining mitochondrial membrane potential (MMP) and suppressing activation of the mitochondria-dependent caspase-9/3 apoptosis pathway. Furthermore, we identified miR-34a, a crucial negative regulator of Bcl-2, as a target for the protective effect of TDB on vascular cells. TDB-induced suppression of miR-34a resulted in a significant upregulation of Bcl-2 protein, MMP maintenance, and the survival of vascular cells following OGD/R. Our findings suggest that targeting miR-34a with the natural product TDB may provide a novel strategy for the treatment of ischemic vascular injuries, and demonstrate the therapeutic potential in targeting miRNAs using appropriate small molecules.