Perioperative neurocognitive disorders (PND) are a common complication in elderly patients following surgery, which not only prolongs the recovery period but also affects their future quality of life and imposes a significant burden on their family and society. Multiple factors, including aging, vulnerability, anesthetic drugs, cerebral oxygen desaturation, and severe pain, have been associated with PND. Unfortunately, no effective drug is currently available to prevent PND. α5 γ-aminobutyric acid subtype A (α5GABAA) receptors have been implicated in cognitive function modulation. Positive or negative allosteric modulators of α5GABAA receptors have been found to improve cognitive impairment under different conditions. Therefore, targeting α5GABAA receptors may represent a promising treatment strategy for PND. This review focuses on preclinical studies of α5GABAA receptors and the risk factors associated with PND, primarily including aging, anesthetics, and neuroinflammation. Specifically, positive allosteric modulators of α5GABAA receptors have improved cognitive function in aged experimental animals. In contrast, negative allosteric modulators of α5GABAA receptors have been found to facilitate cognitive recovery in aged or adult experimental animals undergoing anesthesia and surgery but not in aged experimental animals under anesthesia alone. The reasons for the discordant findings have yet to be elucidated. In preclinical studies, different strategies of drug administration, as well as various behavioral tests, may influence the stability of the results. These issues need to be carefully considered in future studies.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.