Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles. Beyond these hallmark pathological features, the complex pathogenesis of AD involves cellular dysfunctions associated with chronic oxidative stress and neuroinflammation. Central to these inflammatory pathways is the extracellular release of the nuclear protein high-mobility group box 1 (HMGB1) from neurons and microglia. Extracellular HMGB1 disrupts homeostatic and reparative microglial functions, impairing the phagocytic clearance of amyloid-beta and driving neuroinflammation to accelerate AD pathogenesis. Consequently, targeting HMGB1 offers a promising therapeutic strategy for AD. This review examines recent progress and key insights regarding HMGB1-associated neuroinflammatory pathology in AD. We evaluate its regulation across transcriptional upregulation, cellular redistribution, age-related alterations, and Aβ-associated pathology. We further detail the pleiotropic effects of extracellular HMGB1, including neuroinflammation, defective Aβ phagocytic clearance, and genomic instability. Finally, we discuss the potential clinical utility of targeting HMGB1 to mitigate AD progression and provide HMGB1-related perspectives for future studies.