Carotid endarterectomy (CEA) is widely used to treat carotid artery stenosis (CAS). However, the effects of CEA on unilateral CAS-induced cognitive impairment and the underlying mechanism remain poorly understood.Thirteen patients diagnosed with unilateral severe CAS underwent pre- and post-CEA assessments, including 18fluoro-2-deoxy-d-glucose positron emission tomography/magnetic resonance imaging, cognitive assessments, and routine blood tests before and after CEA. Unilateral carotid common artery occlusion and ligation release (reperfusion) surgeries were performed in mice to mimic CAS and CEA. Cognitive function, cerebral blood flow, and white matter damage were evaluated in mice using the Morris water maze test, Doppler flowmetry, laser-speckle imaging, diffusion tensor imaging, Luxol fast blue staining, transmission electron microscopy, and western blot assays post unilateral carotid common artery occlusion and reperfusion. Genomic sequencing of the white matter was performed to explore the potential underlying mechanism. CEA significantly enhanced the Montreal Cognitive Assessment scores in patients with CAS and preoperative cognitive impairment. Moreover, CEA led to notable improvements in cerebral blood flow, energy metabolism, and white matter integrity, while concurrently reducing blood inflammation. In the mouse model, reperfusion surgery alleviated cognitive deficits, increased cerebral blood flow, and alleviated white matter damage following unilateral carotid common artery occlusion. Furthermore, transcriptional surveys have revealed substantial alterations in the upregulation of Nrf2 signaling and metabolic pathways, coupled with the inhibition of neuroinflammation, cellular communication, and immune cell population signaling following reperfusion.CEA ameliorated CAS-induced cognitive dysfunction by improving the cerebral functional structure. These beneficial effects may be attributed to their antioxidant and anti-inflammatory properties.