Glioma, the most common malignant tumor of the central nervous system, has a high postoperative recurrence rate. While Ciprofol is widely used as an anesthetic, its therapeutic potential in glioma treatment remains largely unexplored.Glioma T98G cells were treated with varying concentrations of Ciprofol to assess proliferation, invasion, migration, and apoptosis via CCK-8, Transwell, and flow cytometry assays. Proteomic, phosphoproteomic, and transcriptomic analyses were performed to identify molecular targets and pathways. Molecular docking evaluated the binding of Ciprofol to key kinases, and silencing experiments validated their roles. In vivo, glioma mouse models were used to assess postoperative recurrence via tumor size, fluorescence imaging, and histological analysis.Ciprofol inhibited glioma cell proliferation, invasion, and migration while promoting apoptosis. Proteomic analyses identified MAPK11 and PML as key mediators of Ciprofol's effects. Silencing MAPK11 impaired these effects, while in vivo experiments showed reduced postoperative recurrence via MAPK11-PML phosphorylation.Ciprofol reduces postoperative glioma recurrence by promoting MAPK11-PML phosphorylation, providing novel molecular targets for glioma treatment and suggesting its therapeutic potential beyond anesthesia.© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.