Vascular dementia (VaD), the second cause of dementia, is caused by chronic cerebral hypoperfusion, producing progressive damage to cerebral cortex, hippocampus, and white matter. Ligustilide (LIG), one of the main active ingredients of Angelica sinensis, exerts the neuroprotective effect on neurodegenerative diseases. However, the mechanism remains unclear. An in vivo model of bilateral common carotid artery occlusion and in vitro model of oxygen glucose deprivation (OGD) were employed in this study. LIG (20 or 40 mg/kg/day) was intragastrically administered to the VaD rats for four weeks. The results of the Morris water maze test demonstrated that LIG effectively ameliorated learning and memory deficiency in VaD rats. LIG obviously relieved neuronal oxidative stress damage by increasing the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) and decreasing the level of malondialdehyde (MDA) in VaD rats. Nissl staining showed that LIG increased the number of the Nissl body in VaD rats. After LIG administration, the apoptotic-related protein, Bax, was decreased and Bcl-2 was increased in the hippocampus of VaD rats. Moreover, the expressions of sirtuin 1 (SIRT1) and protein disulfide isomerase (PDI) were decreased, binding immunoglobulin protein (BIP) and phospho-inositol-requiring enzyme-1α (P-IRE1α), X-box binding protein 1 (XBP1s), and C/EBP-homologous protein (CHOP) were increased in VaD rats. After LIG treatment, these changes were reversed. The immunofluorescence results further showed that LIG upregulated the expression of SIRT1 and downregulated the expression of P-IRE1α in VaD rats. In addition, in vitro experiment showed that EX-527 (SIRT1 inhibitor) partly abolished the inhibitory effect of LIG on the IRE1α/XBP1s/CHOP pathway. In conclusion, these studies indicated that LIG could improve cognitive impairment by regulating the SIRT1/IRE1α/XBP1s/CHOP pathway in VaD rats.Copyright © 2022 Dong Peng et al.