Postoperative cognitive dysfunction (POCD) is a serious and common complication induced by anesthesia and surgery. Neuronal apoptosis induced by general anesthetic neurotoxicity is a high-risk factor. However, a comprehensive analysis of general anesthesia-regulated gene expression patterns and further research on molecular mechanisms are lacking. Here, we performed bioinformatics analysis of gene expression in the hippocampus of aged rats that received sevoflurane anesthesia in GSE139220 from the GEO database, found a total of 226 differentially expressed genes (DEGs) and investigated hub genes according to the number of biological processes in which the genes were enriched and performed screening by 12 algorithms with cytoHubba in Cytoscape. Among the screened hub genes,Agt,Cdkn1a,Ddit4, andRhobare related to the neuronal death process. We further confirmed that these genes, especiallyDdit4, were upregulated in the hippocampus of aged mice that received sevoflurane anesthesia.NMDAR, the core target receptor of sevoflurane, rather thanGABAAR, mediates the sevoflurane regulation ofDDIT4expression. Our study screened sevoflurane-regulated DEGs and focused on the neuronal death process to revealDDIT4as a potential target mediated byNMDAR, which may provide a new target for the treatment of sevoflurane neurotoxicity.