Objective To explore the effects of dexamethasone on silent information regulator 1 (SIRT1)/nuclear factor (NF)-κB signaling pathways in rats undergoing isoflurane anesthesia. Methods A total of 40 SD rats were randomly divided into Sham group (no treatment), ISO group (inhalation of 1.4% isoflurane for 4h), 5 Dex Iso group (intraperitoneal injection of 5 mg/kg dexamethasone at 30 minutes before isoflurane inhalation) and 10 Dex Iso group (intraperitoneal injection of 10 mg/kg dexamethasone at 30 minutes before isoflurane inhalation). The cognitive function of rats was evaluated by Morris water maze test and object position recognition test. The morphological changes of hippocampus were observed by HE staining. The apoptosis of neurons in hippocampus was observed by TUNEL staining. The levels of interleukin-6 (IL-6), IL-1β and tumor necrosis factor α (TNF-α) in hippocampus were detected by ELISA. The expressions of cysteine proteinase-3 (caspase-3), caspase-9, SIRT1, NF-κB, phosphorylated (p)-NF-κB and NF-κB inhibitory protein (IκBα) were detected by Western blot. Results Compared with Sham group, escape latency and object memory time were prolonged on the 3rd-5th day were prolonged, the times of crossing the original platform were reduced, apoptosis rate of hippocampus neurons, the relative expression levels of caspase-3 and caspase-9, and levels of IL-6, IL-1β, TNF-α and p-NF-κB/NF-κB were significantly increased, and expression levels of SIRT1 and IκBα were significantly decreased in ISO group (P<0.05). Compared with ISO group, the escape latency and object memory time were shortened on the 4rd-5th day, times of crossing the original platform were increased, the apoptosis rate of hippocampus neurons, the relative expression levels of caspase-3 and caspase-9, and the levels of IL-6, IL-1β, TNF-α and p-NF-κB/NF-κB were significantly decreased, and the expression levels of SIRT1 and IκBα were significantly increased in 10 Dex Iso group (P<0.05). Conclusion Dexamethasone can improve cognitive dysfunction induced by isoflurane anesthesia and reduce neurons apoptosis in rats, which may be related to regulating SIRT1/NF-κB signaling pathways