Cortical spreading depression (CSD) is a key pathological event in various neurological disorders such as migraine and cerebral ischemia. Recent research reveals that the glial-vascular unit (GVU) serves as a central platform regulating the CSD process. This review systematically elucidates the dynamic roles and mechanisms of GVU components in CSD: the dual functions of astrocytes as central hubs; microglia acting as one of initiating cells potentially involved in both damaging and reparative effects; abnormal post-CSD contraction of pericytes mediating sustained capillary hypoperfusion; while functional alterations in the perivascular space and glymphatic system may represent potential factors influencing CSD initiation and recovery. These findings establish the GVU as the core regulatory platform for CSD, whose internal synergy and conflicts determine disease progression. This shifts the research focus from individual components to the entire GVU, providing novel perspectives for comprehensively understanding CSD pathophysiology and developing multi-target synergistic therapeutic strategies.