Background Sevoflurane has obvious side effects during anesthesia, which caused neuronal apoptosis and neuroinflammation. How to reduce Sevoflurane-induced neurotoxicity is an urgent problem to be solved. Objective To assess the role of USP18 in anesthetic Sevoflurane-induced neurotoxicity, detect its effects on neuroinflammation, oxidative stress, and apoptosis, and explore the related potential signaling pathway. Results USP18 alleviated Sevoflurane-induced learning and memory dysfunction and changed distribution of neurons. USP18 also reduced Sevoflurane-induced neuroinflammation. We further found that USP18 reduced the Sevoflurane-induced oxidative stress in the mice model. USP18 also attenuated Sevoflurane-induced neuronal apoptosis. Mechanically, USP18 reduced Sevoflurane-induced neurotoxicity via AKT and NF-κB pathway. Conclusion USP18 was involved in the pathology of Sevoflurane-induced neurotoxicity.