In this review article, we aim to illustrate the biological functions of HMGB1 and the role of this protein in ischemic stroke, as well as fully clarify the mechanisms of HMGB1’s role in stroke pathology, to highlight HMGB1 and pathways which may be potential drug targets in an attempt to provide new prospects and directions for the treatment of ischemic stroke. The gene discussed is HMGB1; the disease is Stroke.