OBJECTIVE To explore the effect and molecular mechanism of nalmefene on postoperative cognitive dysfunction (POCD) in aged rats. METHODS Seventeen-month-old SD rats were randomly divided into control group (Control), model group (Model), model + nalmefene group (Model+Nal), model+nalmefene+EX527 group (Model+Nal+EX527) with 8 rats in each group after one week of acclimatization. The POCD animal models (excluding the Control group) were established by sevoflurane anesthesia and exploratory laparotomy. The rats in Model+Nal group were subcutaneously injected with 0.1 mg·kg^-1 nalmefene hydrochloride 30 min before anesthesia induction. The rats in Model+Nal+EX527 group were injected subcutaneously with 0.1 mg·kg^-1 nalmefene hydrochloride and intraperitoneally with 10 mg·kg^-1 EX527 (Sirt1 inhibitor) 30 min before anesthesia induction. Morris water maze experiment was conducted to analyze the cognitive abilities of rats. Hippocampal tissues were collected 3 d after surgery. The pathological changes of the hippocampus were observed by HE staining. Neuron apoptosis was analyzed by Tunel staining. ELISA method was used to detect the contents of TNF-α and IL-6. The protein expression levels of Bax, Bcl-2, Sirt1, TLR4 and NF-κB p65 were determined by Western blot. RESULTS Compared with the Control group, the cognitive dysfunction was seen, neuronal damage and the proportion of apoptotic neurons in hippocampal DG region were increased, TNF-α and IL-6 contents as well as the expression of Bax, TLR4 and NF-κB p65 were elevated, while the expression of Bcl-2 and Sirt1 was decreased in the Model group (P<0.001). Compared with the Model group, the cognitive ability was enhanced, neuronal damage and the proportion of apoptotic neurons in hippocampal DG region were decreased, TNF-α and IL-6 contents as well as the expression of Bax, TLR4 and NF-κB p65 were reduced, whereas the expression of Bcl-2 and Sirt1 was elevated in the Model+Nal group (P<0.001). Compared with the Model+Nal group, the cognitive ability was suppressed, neuronal damage and the proportion of apoptotic neurons in hippocampal DG region were increased, TNF-α and IL-6 contents as well as the expression of Bax, TLR4 and NF-κB p65 were elevated, while the expression of Bcl-2 and Sirt1 was decreased in the Model+Nal+EX527 group (P<0.001). CONCLUSION Nalmefene can reduce neuroinflammation and neuronal damage, and improve cognitive dysfunction in aged POCD rats through regulating Sirt1/TLR4/NF-κB pathway.