The study investigated the mechanism of ALDH2 in mitochondrial dysfunction and blood-brain barrier (BBB) damage arising from chronic cerebral hypoperfusion (CCH). A rat model of bilateral common carotid artery occlusion (BCCAO) was established and treated with AAV-ALDH2. ALDH2 expression, cognitive function, and levels of inflammation- and oxidative stress-related factors, were examined, followed by observing changes in BBB and mitochondrial functions. A rat neuron model of oxygen glucose deprivation/re-oxygenation (OGD/R) was constructed and treated with AAV-ALDH2 and the SIRT1 inhibitor Sirtinol. 4-HNE, SIRT1, ROS levels, mitochondrial membrane potential (MMP), and ATP production were detected, followed by oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) assays. ALDH2 was down-regulated in BCCAO-modeled rats. In BCCAO-modeled rats, ALDH2 overexpression repressed learning/memory deficits and BBB leakage, elevated SOD and GSH levels, decreased the levels of inflammation-related factors, ROS, 4-HNE, and MDA, and improved mitochondrial morphology. In OGD/R-stimulated neurons, ALDH2 overexpression diminished ROS and 4-HNE levels and ECAR and increased MMP, OCR, and ATP production, which was abrogated by Sirtinol. Overall, ALDH2 up-regulation exerts suppressive effects on BBB damage and mitochondrial dysfunction in CCH via the SIRT1/ROS axis.