<p>Microglia, the resident immune cells of the central nervous system (CNS), play critical roles in maintaining brain homeostasis and responding to neurological insults. Recent advances have fundamentally reshaped our understanding of how microglial mitochondrial metabolism influences neuroinflammation and disease progression. Single-cell transcriptomics has revealed unexpected metabolic heterogeneity, identifying distinct phenotypes such as disease-associated microglia (DAM) and lipid-laden microglia (LLM) that represent not merely activated states but terminal endpoints of metabolic paralysis. These discoveries converge on a unified pathogenic mechanism: mitochondrial quality control failure leads to mitochondrial DNA release, which activates the cGAS–STING pathway to create an “epigenetic lock” that drives sustained neuroinflammation. Interestingly, we highlight that the loss of metabolic flexibility—rather than glycolysis per se—is the true driver of pathology, explaining why the same metabolic shift can be protective during acute injury but pathological when sustained chronically. We critically examine conflicting evidence across Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and ischemic stroke, including the puzzling dual roles of glycolysis, controversies surrounding the experimental autoimmune encephalomyelitis (EAE) model in multiple sclerosis research, and the paradoxical worsening of stroke outcomes following microglial depletion. By synthesizing these mechanistic insights with lessons from failed clinical trials, we identify critical translational gaps—including the lack of longitudinal human data and validated biomarkers—and propose a precision medicine framework focused on restoring mitochondrial dynamics and metabolic flexibility in neurological diseases.</p>