<p>High mobility group box-1 (HMGB1) is a non-histone chromatin-associated transcription factor. HMGB1 has several physiological activities, including developing the central nervous system (CNS) and repairing deoxyribonucleic acid (DNA) damage. HMGB1 is well documented as a significant contributor to neuroinflammation in several conditions, including Alzheimer's disease, Parkinson’s disease, Huntington’s disease, and traumatic brain injury (AD, PD, HD, and TBI). The physiological activities of HMGB1 rely on its presence in either the extracellular or intracellular environment. Moreover, it transforms into a malevolent entity when translocated from the extracellular to intracellular environment via several processes. It governs the interface between histones and DNA, eventually influencing gene expression. Apart from this, the HMGB1 interaction between the receptor for advanced glycation end product and toll-like receptors (RAGE and TLRs) is so well established that it further modulates nuclear factor kappa-light chain-enhancer of activated B-cells (NF-κB), which is linked to production of interleukin-18, interleukin-1 beta, and tumour necrosis factor-alpha (IL-18, IL-1β, and TNF-α) when it functions as a damage-associated molecular pattern (DAMP). However, there are currently no effective targeted medicines available. Numerous phytochemicals, including alkaloids, terpenoids, and antioxidants, may alleviate HMGB1-targeted neuroinflammation. Conversely, HMGB1 inhibitors, such as antibody, peptide, and ribonucleic acid (RNA)-based treatments, may be more effective than conventional therapy to mitigate HMGB1-associated neuroinflammation. This review emphasized the possibility of targeted natural and synthetic biomolecules in addressing HMGB1-associated brain diseases.</p>