High mobility group box-1 (HMGB1) is a nuclear protein that is expressed in almost all eukaryotic cells. In the nucleus, it maintains nuclear homeostasis and promotes gene transcription. HMGB1 can be passively released into the extracellular milieu after cell necrosis or actively secreted by activated immune cells. HMGB1 has several receptors such as Toll-like receptor 2, Toll-like receptor 4, and the receptor for advanced glycation end products. After brain injury, HMGB1 is released early from neural cells and contributes to the initial stages of the inflammatory response. However, surprisingly, HMGB1 can mediate beneficial effects during the course of stroke recovery. The biphasic biological property of extracellular HMGB1 may be related to the redox modifications of its cysteine residues. This review discusses the emerging roles of HMGB1 in several stroke models, as well as its potential role as a therapeutic target for stroke patients.