Background: Recent studies have showed that high-mobility group box 1 (HMGB1), a proinflammatory cytokine, is well-received by many innate immune system cells. It was initially thought that this protein resided in the nucleus, where it was discovered. Systemic lupus erythematosus (SLE) is a chronic inflammatory illness characterized by the release of HMGB1 from both necrotic and apoptotic cells as a result of damage pattern. Objective: Review of the literature on role and correlations of High-Mobility Group Box 1 protein (HMGB1) among pathogenesis of Systemic Lupus Erythematosus. Methods: We looked for data on High-Mobility Group Box 1 Protein, and Systemic Lupus Erythematosus, in medical journals and databases like PubMed, Google Scholar, and Science Direct. However, only the most recent or extensive study was taken into account between August 2000 and January 2023. References from related works were also evaluated by the writers. There are not enough resources to translate documents into languages other than English, hence those documents have been ignored. It was generally agreed that documents such as unpublished manuscripts, oral presentations, conference abstracts, and dissertations did not qualify as legitimate scientific study. Conclusion: Multiple disease mechanisms in SLE have been demonstrated to be influenced by HMGB1. Because of its dual role as a DAMP and a cytokine, HMGB1 can trigger harmful responses from both the adaptive as well as innate immunity systems. As the disease progresses in SLE, local cells in the damaged organs also interact with HMGB1. Understanding SLE and creating effective treatments will benefit greatly from research into the multiple roles HMGB1 plays in the immune system.