Alzheimer’s disease is characterized by amyloid-β (Aβ)–induced synaptic dysfunction and N -methyl- d -aspartate (NMDA) receptor–dependent calcium dysregulation, and inorganic polyphosphate (polyP), a platelet-enriched polymer released upon platelet activation, has emerged as a potential modulator of neuronal survival. Primary rat neuronal cultures and PC12 pheochromocytoma cells were exposed to the neurotoxic Aβ fragment Aβ(25–35), following a 2–5 day pre-incubation to induce its toxic conformation; neuronal apoptosis, NMDA receptor–mediated calcium influx, and the mechanistic basis of polyP action were assessed in the presence of sodium polyphosphate (Na-polyP), including experiments with calcium-chelating polyP coacervates formed in combination with serotonin, and the release kinetics of three polyP-based brain-targeted formulations were characterized. Pre-incubated Aβ(25–35) at 10 µM induced apoptotic neuronal death within 3 days, whereas coincubation with Na-polyP (50 µg/mL) abolished Aβ-induced neurotoxicity and significantly attenuated glutamate-evoked NMDA receptor–dependent calcium influx; mechanistic analyses demonstrated that Na-polyP forms calcium-chelating coacervates, promoted by serotonin at physiological Ca²⁺ concentrations, and that polyP nanogels, nanoparticles and micelle-based formulations exhibit controlled release profiles. These data identify calcium chelation via polyP coacervate formation as a key mechanism underlying protection against Aβ-induced NMDA receptor sensitization and neuronal death, and suggest that polyP-based strategies may provide a mechanistically grounded approach for therapeutic intervention in Alzheimer’s disease.