<p>In this study, we investigated the immunomodulatory effects of melatonin on B-cell maturation and its potential to mitigate immunodeficiency following transient focal cerebral ischemia in mice. Transient middle cerebral artery occlusion (MCAO) was induced in adult C57BL/6 mice, followed by melatonin administration. We evaluated the effects of melatonin on neutrophil infiltration, macrophage and microglial activation in the ischemic brain, and B-cell maturation in both the central nervous system and peripheral blood. Melatonin treatment significantly reduced pro-inflammatory cell infiltration in the ischemic hemisphere and promoted B-cell maturation, reflecting robust immunomodulatory activity. These immune changes coincided with improved neurological outcomes and reduced cerebral edema. Collectively, our findings suggest that melatonin may serve as a promising therapeutic candidate in ischemic stroke, addressing both immunodeficiency and neuronal injury.</p> Graphical Abstract <p></p>