<p>Postoperative Cognitive Dysfunction (POCD) is one of the most common perioperative complications, which has already become a significant challenge for postoperative patient management. Esketamine has demonstrated promising therapeutic potential for POCD; however, its specific mechanism remains incompletely understood. This study aimed to investigate the mechanism of esketamine in treating POCD by integrating network pharmacology, in vivo experiments, and in vitro experiments. In this study, network pharmacology combined with experimental validation was employed to explore the underlying mechanisms by which esketamine ameliorates POCD. Initially, the key targets and pathways were analyzed using network pharmacology. Behavioral tests were performed to evaluate postoperative motor and cognitive function in mice. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of inflammatory factors. Western blotting was applied to measure the expression of proteins related to signaling pathways, and immunofluorescence staining was conducted to assess microglial activation. A total of 41 potential targets and 56 signaling pathways were identified for POCD intervention using network pharmacology analysis. In vivo experiments showed that esketamine improved postoperative memory and cognitive function in mice, reduced neuroinflammatory responses in the hippocampus, and inhibited microglial M1 polarization. Further experiments revealed that this protective effect was mediated by regulation of the PI3K/AKT/GSK3β signaling pathway. This study demonstrates that the anti-neuroinflammatory effect of esketamine in POCD is mediated by its activation of the PI3K-AKT-GSK3β pathway, which suppresses excessive microglial activation.</p>