BACKGROUND: Sevoflurane (SEV), a widely used inhalational anesthetic, multiple SEV exposures has been implicated in cognitive impairment, particularly in neonates. However, the mechanisms underlying SEV-induced cognitive impairment not fully understood. METHODS: Neonatal mice or murine microglial line BV-2 cells were exposed to SEV. Morris water maze and novel object recognition tests were used for measuring the cognitive function of mice. Histological examination and immunofluorescence staining were conducted to evaluate hippocampal morphology and the lactylated proteins in microglia, respectively. Cell pyroptosis was measured by flow cytometry and transmission electron microscope, and cytokine levels were detected using ELISA. Protein and gene expression were analyzed through western blot and RT-PCR. The interaction of proteins was verified by CHIP or RIP assays. RESULTS: SEV induces significant cognitive impairment and reduces both histone lactylation and YTH domain-containing family protein 3 (YTHDF3) expression in the hippocampal tissues of neonatal mice. A decrease in histone lactylation and YTHDF3 expression is accompanied by increased cell pyroptosis and inflammation were observed in SEV-treated BV-2 cells. SEV modulates YTHDF3 expression via histone lactylation, thereby influencing N6-methyladenosine (m6A)-mediated peroxiredoxin 3 (PRDX3) translation and the subsequent activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome mediated pyroptosis in BV-2 cells. Overexpression of YTHDF3 or PRDX3 counteract the SEV-induced promotion of pyroptosis and inflammation in BV-2 cells. Furthermore, histone lactylation enhances YTHDF3 expression and mitigates SEV-induced cognitive dysfunction in neonatal mice, whereas downregulation of YTHDF3 diminishes this protective effect. CONCLUSION: Our findings elucidate that histone lactylation mitigates SEV-induced cognitive impairment by regulating YTHDF3/PRDX3-mediated microglial pyroptosis in neonatal mice. These insights offer a novel understanding of the molecular mechanisms underlying SEV-induced neurotoxicity in neonates.