Objective To explore the role of cognitive reserve in predicting cognitive impairment in patients with acute ischemic stroke (AIS). Methods From Nov. 2021 to Oct. 2022, a total of 291 AIS patients admitted to Neurovascular Center of The First Affiliated Hospital of Naval Medical University (Second Military Medical University) and Stroke Center of Air Force Hospital of PLA Eastern Theater Command were selected by convenience sampling method. Cognitive reserve and cognitive function were assessed using cognitive reserve index questionnaire and Montreal cognitive assessment, respectively. General information was obtained from the patients’ medical records or bedside assessment by neurologists. Multivariate binary logistic regression was used to analyze the predictive effect of cognitive reserve on cognitive impairment in AIS patients. Results The average age of 291 AIS patients was (65.9±10.4) years old. The National Institutes of Health stroke scale (NIHSS) score at admission was 5 (2, 10), the total scores of cognitive reserve and cognitive function were 97±16 and 23 (17, 27), respectively, and 218 patients (74.9%) had cognitive impairment. After adjusting for age, type of residency, NIHSS score at admission, diabetes mellitus, degree of cerebral vascular stenosis, and depression symptom, cognitive reserve was a protective factor for post-stroke cognitive impairment; AIS patients with high cognitive reserve level were 0.156 times more likely to have cognitive impairment than those with low cognitive reserve level (95% confidence interval ［CI］ 0.045-0.538, P＝0.003) and patients with moderate level of cognitive reserve were 0.272 times more likely to have cognitive impairment than those with low cognitive reserve level (95% CI 0.113-0.654, P＝0.004). Conclusion A higher level of cognitive reserve is a protective factor for AIS patients with cognitive impairment. Improving the level of cognitive reserve is expected to be one of the potential strategies for early cognitive intervention in stroke patients.