HMGB1 is a key player in neuroinflammation following brain ischemia and ischemia-reperfusion injury. It is a damage-associated molecular pattern (DAMP) that is passively released by necrotic cells and actively secreted by immune cells, glial cells, platelets, and endothelial cells. HMGB1 is involved in the pathogenesis of atherosclerosis, thromboembolism, and detrimental inflammation during the early phases of ischemic stroke. It also contributes to neurovascular remodeling and functional recovery in later stages. HMGB1 mediates hemorrhagic transformation by facilitating neuroinflammation, directly compromising the blood-brain barrier, and enhancing MMP9 secretion through its interaction with rtPA. As a systemic inflammatory factor, HMGB1 is implicated in post-stroke depression and an elevated risk of stroke-associated pneumonia. HMGB1 influences 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, which will pave the way for developing new neuroprotective drugs, reducing post-stroke neuroinflammation, and expanding the thrombolysis time window. HMGB1 is a non-histone DNA-binding protein with three structural domains and a 30-amino acid long c-segment tail. Its redox state is essential for its role in regulating inflammatory responses and autophagy. Redox modifications at cysteine residues regulate HMGB1's functional properties. HMGB1 is released passively in early post-stroke cell necrosis and actively in the late phase of stroke. Its secretion is regulated by various factors, including acetylation, methylation, N-glycosylation, phosphorylation, and oxidation. HMGB1 is released from necrotic cells and activated macrophages, inducing the recruitment of inflammatory cells and mediating signaling between NK cells, dendritic cells, T cells, and macrophages. Platelets are an essential source of active HMGB1 secretion, and HMGB1 is critical in the acute phase of stroke to produce neutrophil extracellular traps (NETs) that exacerbate post-stroke outcomes. HMGB1 promotes monocyte accumulation and activation via the receptor for advanced glycosylation end products (RAGE) and Toll-like receptor 2 (TLR2). It facilitates RAGE-mediated formation of prethrombotic NETs, where the combined effects of coagulation and inflammation lead to thrombosis. HMGB1 induces autophagy, which is aHMGB1 is a key player in neuroinflammation following brain ischemia and ischemia-reperfusion injury. It is a damage-associated molecular pattern (DAMP) that is passively released by necrotic cells and actively secreted by immune cells, glial cells, platelets, and endothelial cells. HMGB1 is involved in the pathogenesis of atherosclerosis, thromboembolism, and detrimental inflammation during the early phases of ischemic stroke. It also contributes to neurovascular remodeling and functional recovery in later stages. HMGB1 mediates hemorrhagic transformation by facilitating neuroinflammation, directly compromising the blood-brain barrier, and enhancing MMP9 secretion through its interaction with rtPA. As a systemic inflammatory factor, HMGB1 is implicated in post-stroke depression and an elevated risk of stroke-associated pneumonia. HMGB1 influences 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, which will pave the way for developing new neuroprotective drugs, reducing post-stroke neuroinflammation, and expanding the thrombolysis time window. HMGB1 is a non-histone DNA-binding protein with three structural domains and a 30-amino acid long c-segment tail. Its redox state is essential for its role in regulating inflammatory responses and autophagy. Redox modifications at cysteine residues regulate HMGB1's functional properties. HMGB1 is released passively in early post-stroke cell necrosis and actively in the late phase of stroke. Its secretion is regulated by various factors, including acetylation, methylation, N-glycosylation, phosphorylation, and oxidation. HMGB1 is released from necrotic cells and activated macrophages, inducing the recruitment of inflammatory cells and mediating signaling between NK cells, dendritic cells, T cells, and macrophages. Platelets are an essential source of active HMGB1 secretion, and HMGB1 is critical in the acute phase of stroke to produce neutrophil extracellular traps (NETs) that exacerbate post-stroke outcomes. HMGB1 promotes monocyte accumulation and activation via the receptor for advanced glycosylation end products (RAGE) and Toll-like receptor 2 (TLR2). It facilitates RAGE-mediated formation of prethrombotic NETs, where the combined effects of coagulation and inflammation lead to thrombosis. HMGB1 induces autophagy, which is a