Stroke is a significant health issue in China, characterized by high morbidity, recurrence, disability, and mortality. Ultra-early administration of rtPA is crucial for restoring perfusion in acute ischemic stroke but increases the risk of hemorrhagic transformation. High-mobility group box 1 (HMGB1) plays a pivotal role in neuroinflammation following brain ischemia and ischemia-reperfusion. HMGB1 is released passively by necrotic cells and actively secreted by immune cells, glial cells, platelets, and endothelial cells, acting as a damage-associated molecular pattern (DAMP). It is involved in atherosclerosis, thromboembolism, and detrimental inflammation during the early phases of ischemic stroke. Additionally, HMGB1 contributes to neurovascular remodeling and functional recovery in later stages. HMGB1 mediates hemorrhagic transformation by facilitating neuroinflammation, compromising the blood-brain barrier, and enhancing MMP9 secretion through its interaction with rtPA. As a systemic inflammatory factor, HMGB1 is also implicated in post-stroke depression and an elevated risk of stroke-associated pneumonia. The role of HMGB1 extends to influencing the pathogenesis of ischemia by polarizing various subtypes of immune and glial cells, including mediating excitotoxicity, autophagy, MMP9 release, NET formation, and autocrine trophic pathways. Given its multifaceted role, HMGB1 is recognized as a crucial therapeutic target and prognostic marker for ischemic stroke and hemorrhagic transformation. This review summarizes the structure and redox properties, secretion and pathways, regulation of immune cell activity, and the role of pathophysiological mechanisms in stroke and hemorrhagic transformation, aiming to pave the way for developing new neuroprotective drugs and reducing post-stroke neuroinflammation.Stroke is a significant health issue in China, characterized by high morbidity, recurrence, disability, and mortality. Ultra-early administration of rtPA is crucial for restoring perfusion in acute ischemic stroke but increases the risk of hemorrhagic transformation. High-mobility group box 1 (HMGB1) plays a pivotal role in neuroinflammation following brain ischemia and ischemia-reperfusion. HMGB1 is released passively by necrotic cells and actively secreted by immune cells, glial cells, platelets, and endothelial cells, acting as a damage-associated molecular pattern (DAMP). It is involved in atherosclerosis, thromboembolism, and detrimental inflammation during the early phases of ischemic stroke. Additionally, HMGB1 contributes to neurovascular remodeling and functional recovery in later stages. HMGB1 mediates hemorrhagic transformation by facilitating neuroinflammation, compromising the blood-brain barrier, and enhancing MMP9 secretion through its interaction with rtPA. As a systemic inflammatory factor, HMGB1 is also implicated in post-stroke depression and an elevated risk of stroke-associated pneumonia. The role of HMGB1 extends to influencing the pathogenesis of ischemia by polarizing various subtypes of immune and glial cells, including mediating excitotoxicity, autophagy, MMP9 release, NET formation, and autocrine trophic pathways. Given its multifaceted role, HMGB1 is recognized as a crucial therapeutic target and prognostic marker for ischemic stroke and hemorrhagic transformation. This review summarizes the structure and redox properties, secretion and pathways, regulation of immune cell activity, and the role of pathophysiological mechanisms in stroke and hemorrhagic transformation, aiming to pave the way for developing new neuroprotective drugs and reducing post-stroke neuroinflammation.