High mobility group box 1 (HMGB1) is a ubiquitous and highly conserved non-histone DNA-binding protein with different biological functions according to its subcellular localization. It is widely believed that HMGB1, which is released into the extracellular space, plays a key role in the inflammatory response. In recent years, numerous studies have shown that the development of various neurological diseases such as epilepsy, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), cerebrovascular disease and traumatic brain injury (TBI) are inextricably linked to inflammation. We will review the mechanisms of HMGB1 and its receptors in nervous system inflammation to provide a basis for further development of new HMGB1-based therapies.