Neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, are increasingly recognized as complex neuroimmune conditions rather than purely neuron-centric diseases. Although classical frameworks have emphasized protein aggregation, synaptic dysfunction, and progressive neuronal loss, these mechanisms alone do not fully explain disease heterogeneity or the limited efficacy of current disease-modifying therapies. Emerging evidence suggests that chronic neuroinflammation represents a central and sustained driver of neurodegeneration, acting through tightly interconnected neuronal, glial, and vascular pathways. At the mechanistic level, persistent activation of innate immune signaling—particularly microglial priming and NLRP3 inflammasome activation with downstream IL-1β and IL-18 signaling—establishes a chronic pro-inflammatory milieu within the central nervous system. Misfolded protein species, including amyloid-β and tau, further amplify immune activation by functioning as damage-associated molecular patterns, thereby linking proteinopathy with innate immune responses. Concurrently, progressive disruption of the blood–brain barrier facilitates bidirectional communication between the central and peripheral immune systems, enabling systemic inflammation to exacerbate ongoing neurodegenerative processes. Together, these mechanisms form a self-reinforcing neuroimmune loop that may contribute to disease initiation and progression. From a translational perspective, this integrated framework highlights the limitations of therapeutic strategies that primarily target neurotransmitter imbalance or protein aggregation. Instead, disease modification may require interventions that directly modulate neuroimmune pathways, including regulation of microglial activation states, inhibition of inflammasome signaling, and restoration of blood–brain barrier integrity. Importantly, such approaches necessitate a shift toward mechanism-guided clinical development supported by biomarkers reflecting immune activation, glial reactivity, and neurovascular dysfunction. This may enable improved patient stratification and identification of biologically distinct disease subtypes with differential therapeutic responsiveness. Overall, reframing neurodegeneration as a dynamic and interconnected neuroimmune process provides a more comprehensive understanding of disease pathogenesis and offers a rational foundation for developing mechanism-based therapeutic strategies aimed at modifying disease progression rather than merely alleviating symptoms