Abstract: Chronic cerebral hypoperfusion (CCH) is a major contributor to vascular cognitive impairment (VCI), often resulting in progressive learning and memory deficits. Quercetin (Qu), a natural flavonoid with potent anti-inflammatory and antioxidant properties, demonstrates neuroprotective potential against ischemic injury, yet its mechanism of action remains incompletely understood. In this study, a rat model of CCH was established by bilateral common carotid artery occlusion, followed by Qu administration at doses of 20, 40, and 80 mg/kg. In parallel, HT22 cells subjected to oxygen-glucose deprivation (OGD) were treated with Qu at 5, 10, or 20 μM. Behavioral tests, histological staining, ELISA, and Western Blot were used to assess cognitive performance, neuronal injury, lysosomal activity, NF-κB pathway activation, and inflammatory cytokine levels. Hippocampal RNA sequencing was also performed. Our results demonstrate that Qu greatly improved cognitive performance and attenuated neuronal damage in both the cerebral cortex and hippocampus. Mechanistically, Qu improved lysosomal function and suppressed NF-κB-mediated neuroinflammatory response, leading to less production of pro-inflammatory cytokines. Notably, co-administration of a lysosomal inhibitor attenuated the neuroprotective effects of Qu, underscoring the functional importance of lysosomal activation. In conclusion, Qu alleviates CCH-induced cognitive decline and neurodegeneration by restoring lysosomal function and inhibiting NF-κB-driven neuroinflammation. These findings support the therapeutic potential of Qu for VCI and provide a rationale for its further development as a neuroprotective agent.