Research context reveals that major depressive disorder (MDD), as a prevalent chronic relapsing psychiatric condition affecting up to one-third of patients with treatment resistance, necessitates urgent development of novel therapeutic agents. Emerging evidence implicates neuroinflammatory mechanisms in MDD pathophysiology, while the antidepressant potential of Ganoderic acid A (GAA), a triterpenoid compound derived from Ganoderma lucidum, particularly through modulation of lipopolysaccharide (LPS)-induced depression-like behaviors via acute neuroinflammation suppression remains underexplored. This study demonstrates for the first time that GAA administration significantly inhibits cerebral inflammatory activity and exhibits antidepressant properties in LPS-challenged murine models. Experimental protocols involved male C57BL/6 mice receiving intraperitoneal LPS injections (2 mg/kg) to establish depression-like phenotypes, with control and treatment groups administered saline or GAA (2.5 mg/kg) respectively. Behavioral assessments incorporating sucrose preference tests, forced swimming assays, and tail suspension evaluations were conducted. Neurobiological analyses quantified prefrontal cortex (PFC) protein expression of Iba1, iNOS, and GFAP through immunofluorescence techniques, with parallel measurements of caspase-1 and IL-1 beta levels using comparable methodology. Inflammatory cell infiltration in PFC regions was histologically evaluated via hematoxylin-eosin staining protocols.Key findings demonstrate that GAA intervention not only ameliorated LPS-induced depression-like behavioral manifestations but crucically modulated neuroinflammatory pathways through downregulation of microglial and astrocytic activation states in the PFC. Specific reductions in caspase-1 and IL-1 beta inflammatory mediators were quantitatively confirmed, substantiating the compound's mechanism of action through targeted neuroimmune regulation. These results provide experimental validation for GAA's therapeutic potential as an antidepressant agent operating via neuroinflammation suppression paradigms, offering critical insights for developing novel MDD treatments targeting inflammatory pathomechanisms.