Neuroinflammation　is　a　key　driver　of　neurological　disorders.　Evodiamine　(EVO),　an　alkaloid　from　the　traditional　Chinese　herb　Evodia　rutaecarpa,　possesses　potent　biological　activities,　notably　anticancer　and　anti-inflammatory　effects.　This　study　investigates　EVO＇s　potential　to　attenuate　LPS-induced　neuroinflammation,　focusing　on　identifying　its　therapeutic　targets　and　mechanisms　of　action.　EVO　treatment　significantly　improved　mitochondrial　function　and　reduced　oxidative　stress　in　LPS-stimulated　BV2　cells,　while　also　lowering　levels　of　pro-inflammatory　factors　(IL-6,　NO,　IL-1　beta)　in　brain　organoids.　In　mice,　EVO　treatment　alleviated　behavioral　abnormalities,　especially　in　cognition　and　memory,　and　lowered　hippocampal　inflammation　marker　levels.　To　elucidate　the　critical　mechanisms　by　which　EVO　exerts　its　anti-inflammatory　effects,　we　analyzed　LPS-induced　inflammatory　injury　in　BV2　cells　and　used　transcriptomics　to　investigate　whether　EVO　modulates　the　C/EBP-beta　signaling　pathway.　Further　validation　using　si-C/EBP-beta　confirmed　EVO＇s　regulatory　effect　on　the　C/EBP-beta-COX2　axis,　showing　that　knockdown　significantly　reduced　pro-inflammatory　factor　expression,　thereby　providing　neuroprotection.　Moreover,　molecular　docking　and　dynamics　simulations　confirmed　a　stable　interaction　between　EVO　and　C/EBP　beta,　supporting　its　role　in　attenuating　LPS-induced　neuroinflammation.　In　summary,　these　findings　suggest　that　EVO　regulates　inflammation-related　pathways　by　targeting　the　C/EBP-beta-COX2　axis,　offering　neuroprotective　benefits　and　mitigating　neuroinflammatory　responses.