<p>High Mobility Group A (HMGA) proteins function as non-histone chromatin-associated architectural regulators that modulate gene transcription by modifying chromatin structure rather than binding DNA in a sequence-specific manner. By altering chromatin conformation, HMGA proteins coordinate complex transcriptional programs essential in both physiological and pathological conditions. This review highlights their emerging roles in the context of the nervous system, brain tumorigenesis, and neurodegeneration. We discuss how HMGA-mediated chromatin remodeling and transcriptional regulation influence neurodevelopmental processes, regulating neural stem cell proliferation, differentiation, and lineage specification. We also highlight evidence linking HMGA dysregulation to malignant transformation and progression of brain tumors, where these proteins support oncogenic transcriptional networks. Finally, we explore their possible involvement in molecular pathways associated with neurodegenerative disorders. By integrating findings from developmental neurobiology, oncology, and neurodegeneration research, we aim to provide a comprehensive overview of HMGA proteins as pivotal regulators of neural homeostasis and highlights their potential as biomarkers and therapeutic targets in neurological diseases.</p>