OBJECTIVE To explore the role of NLRP3 inflammasome-mediated ferroptosis in sevoflurane (Sev) induced postoperative cognitive dysfunction (POCD) in rats. METHODS The POCD rat model was established by 4% Sev inhalation anesthesia and abdominal exploration. Firstly, 18-20-month-old SD rats were randomly divided into control group and Sev anesthesia group, with 10 rats in each group. Secondly, SD rats were randomly divided into control group, NLRP3 inflammasome inhibitor group (MCC950), Sev group, and Sev+MCC950 group, with 10 rats in each group. The rats in MCC950 group and Sev+MCC950 group were intraperitoneally injected with 3 mg·kg^-1 MCC950 at 1 h before anesthesia. The rats in the control group and Sev group were intraperitoneally injected with the same amount of normal saline. The learning and memory function of the rats was detected by Morris water maze test, the histopathological changes of hippocampus was observed by HE staining, the apoptosis of hippocampal neurons was detected by TUNEL, Prussian blue staining was used to detect iron deposits in the hippocampus, and the expressions of NLRP3 inflammasome-related proteins and ferroptosis-related proteins in hippocampus were detected by Western blot. Detection of oxidative stress levels in hippocampal tissue by ELISA, the content of Fe²⁺ was detected by colorimetry, and reactive oxygen species (ROS) levels were detected by DHE staining. RESULTS Compared with the control group, there were no significant differences in learning and memory function, hippocampal tissue structure, oxidative stress, ROS and Fe²⁺ levels, NLRP3 inflammasome-related proteins and ferroptosis-related proteins expression in MCC950 group (P>0.05). In the Sev group and Sev+MCC950 group of rats, there were significant learning and memory dysfunction and pathological injury of hippocampus, the activities of SOD and GSH in hippocampus were significantly decreased, the levels of MDA, ROS and Fe²⁺ were significantly increased, and the expressions of NLRP3 inflammasome related proteins and ACSL4 proteins were significantly increased, the protein expressions of SLC7A11 and GPX4 were significantly decreased (P<0.05). Compared with the Sev group, the learning and memory function of rats and the degree of pathological damage of hippocampal tissue were significantly alleviated, the activities of SOD and GSH in hippocampal tissue were significantly increased, the levels of MDA, ROS and Fe²⁺ were significantly decreased, and the expressions of NLRP3 inflammasome-related proteins and ACSL4 proteins were significantly decreased, the protein expressions of SLC7A11 and GPX4 were significantly increased in the Sev+MCC950 (P<0.05). CONCLUSION Sev induces POCD in rats, and its mechanism may be related to the activation of NLRP3 inflammasome-induced neuronal ferroptosis in the hippocampus.