This study investigates the role of serglycin (SRGN), a proteoglycan expressed in immune cells, in microglial activation and ischemic stroke. SRGN was found to be significantly upregulated in the ischemic brains of mice, particularly in microglia. Exogenous SRGN supplementation worsened ischemic brain injury and amplified post-stroke neuroinflammation, while SRGN gene knockout had the opposite effect. SRGN promoted microglial proinflammatory activation both in vivo and in vitro, and this effect was mediated by its interaction with the CD44 receptor. Mechanistically, SRGN activated the NF-κB p65 signaling pathway and increased glycolysis in microglia. These findings suggest that SRGN acts as a novel therapeutic target in microglia-mediated neuroinflammation following ischemic stroke.This study investigates the role of serglycin (SRGN), a proteoglycan expressed in immune cells, in microglial activation and ischemic stroke. SRGN was found to be significantly upregulated in the ischemic brains of mice, particularly in microglia. Exogenous SRGN supplementation worsened ischemic brain injury and amplified post-stroke neuroinflammation, while SRGN gene knockout had the opposite effect. SRGN promoted microglial proinflammatory activation both in vivo and in vitro, and this effect was mediated by its interaction with the CD44 receptor. Mechanistically, SRGN activated the NF-κB p65 signaling pathway and increased glycolysis in microglia. These findings suggest that SRGN acts as a novel therapeutic target in microglia-mediated neuroinflammation following ischemic stroke.