Depressive disorder (DD) ranks among the most prevalent, burdensome, and costly psychiatric conditions globally. It manifests through a range of emotional, cognitive, somatic, and behavioral symptoms. Mesenchymal Stem Cells (MSCs) have garnered significant attention due to their therapeutic potential via immunomodulation in neurological disorders. Our research indicates that MSCs treatment demonstrates a notable effect on a Chronic Unpredictable Mild Stress (CUMS)-induced DD model in mice, surpassing even Fluoxetine in its antidepressant efficacy. MSCs mitigate DD by inhibiting central nervous system inflammation and facilitating the conversion of microglial cells into an Arg1