The traditional neuron-centric model of brain disorders has attributed neurodegeneration primarily to intrinsic neuronal pathologies such as protein aggregation and synaptic failure in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, and amyotrophic lateral sclerosis, and has often been extended to other CNS conditions such as multiple sclerosis, traumatic brain injury, and autism spectrum disorder. However, accumulating evidence highlights glial cells—microglia, astrocytes, and oligodendrocytes—as central drivers of neuroinflammation and disease progression, fundamentally revising this view. Microglia, the brain’s resident immune cells, rapidly sense pathological signals such as amyloid-β and α-synuclein through pattern-recognition receptors (e.g., TLR4) and inflammasome signaling (e.g., NLRP3). This sensing induces a shift from homeostatic surveillance to disease-associated pro-inflammatory states marked by increased release of cytokines such as tumor necrosis factor-alpha, IL-1β, and IL-6. Activated microglia, in turn, can promote reactive astrocytosis, characterized by elevated GFAP and complement C3, which may impair amyloid clearance, disrupt the blood–brain barrier, and contribute to neurotoxicity through reactive oxygen species and glutamate dysregulation. Sustained crosstalk among glial cells via extracellular vesicles and connexin-mediated signaling can amplify inflammation and counter-regulatory neuronal signals. In AD, early protective microglial phagocytosis gives way to plaque-associated dysfunction, accelerating tau pathology and synaptic loss, whereas in PD, α-synuclein-induced glial activation can promote inflammasome-dependent pyroptosis and dopaminergic neuron degeneration. Similar glia-driven inflammatory cycles contribute to other neurodegenerative disorders and may link disease progression to gut–brain–immune interactions. Therapeutic strategies targeting glial polarization, particularly inhibition of the NLRP3 inflammasome, offer promise by restoring neuroprotective functions without broad immunosuppression. This review emphasizes the dual roles of glia and supports integrated neuro-glial models for precision therapies in brain disorders.