BACKGROUND: Depression is a complex neuropsychiatric disorder involving neuroinflammation, synaptic dysfunction, and neurotransmitter dysregulation. Recent studies have highlighted the therapeutic potential of short-acting anesthetics in the treatment of depression. Ciprofol, a novel intravenous anesthetic with rapid onset and recovery, shows promise, although its antidepressant mechanisms remain underexplored. METHODS: We induced a depressive-like phenotype in mice using a 5-week chronic unpredictable mild stress (CUMS) protocol. Following model establishment, the mice received intraperitoneal injections of ciprofol (25 mg/kg) for 7 days. Behavioral assessments included the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). To investigate neuroinflammation and microglial activation in the prefrontal cortex (PFC), we employed immunofluorescence staining, three-dimensional reconstruction, and quantitative real-time PCR (qRT-PCR). Synaptic structural changes were assessed using Western blot, three-dimensional reconstruction, and Golgi staining. Furthermore, transcriptome sequencing and Western blot were performed to elucidate the potential mechanisms underlying the antidepressant effects of ciprofol. RESULTS: Ciprofol treatment alleviated CUMS-induced depressive behaviors, as evidenced by reduced immobility time and increased sucrose preference. Ciprofol suppressed PFC microglial activation and downregulated pro-inflammatory cytokines, while preserving synaptic integrity by inhibiting microglia-mediated synaptic phagocytosis. Mechanistic studies suggested that ciprofol's antidepressant effect might be mediated by PPARα activation, which potentially triggers the ERK/CREB pathway, as indicated by transcriptome analysis and Western blot. CONCLUSION: Ciprofol can alleviate the depressive-like behaviors in CUMS mice by inhibiting the inflammatory response and reducing synaptic loss, and the mechanism may be related to the activation of the PPARα-mediated ERK/CREB pathway.