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Background: Postoperative cognitive dysfunction induced by anesthetics commonly occurs in elderly patients. This study aimed to evaluate the protective role of trametenolic acid B (TAB) in sevoflurane-induced cognitive impairments, and explore the underlying mechanisms., Methods: Animal and cell experiments were performed in rats, differentiated PC12 and HAPI cells by exposing to 2% sevoflurane for 5 h. Different concentration (20, 40 and 80 µg/mL) of TAB was administrated in rats and cells. The cognitive function of rats was evaluated using the Morris water maze test and fear conditioning test. The cell proliferation and apoptosis were investigated using a CCK-8 assay and the flow cytometry. Pro-inflammatory cytokines in microglia were measured using ELISA kits. A miRNA microarray assay was conducted to screen differentially expressed miRNAs by TAB in both PC12 and HAPI cells. The luciferase reporter assay and western blot assay were used to assess the E2F1/CCNA2 and NF-κB pathways., Results: TAB significantly alleviated sevoflurane-induced cognitive impairments in rats, improved PC12 cell viability, and inhibited the neuroinflammation of HAPI cells. miR-329-3p was downregulated in PC12 cells but upregulated in HAPI cells by TAB treatment, which mediated the effects of TAB on neurotoxicity and neuroinflammation. E2F1 and NF-κB P65 were two targets of miR-329-3p, and the E2F1/CCNA2 and NF-κB pathways were inhibited by miR-329-3p in PC12 and HAPI cells, respectively., Conclusions: All the results provide evidence for the protective role of TAB against sevoflurane-induced cognitive impairments, which was achieved by alleviating neurotoxicity and neuroinflammation through differentially regulating miR-329-3p in neurons and microglia., (© 2022. The Author(s).)