Glutamate-mediated excitotoxicity is a central driver of neurodegeneration and represents a shared pathogenic mechanism across neurodegenerative diseases and epilepsy, with N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid recep-tors (AMPARs) occupying central roles in synaptic plasticity, Ca²⁺ signalling, and neuronal survival. Dysregulation of these receptors disrupts the balance between pro-survival and pro-death pathways, accelerating neuronal loss in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lat-eral sclerosis (ALS), Huntington's disease (HD), and epilepsy. Disease-specific triggers converge on common patterns of receptor dysregulation, including a shift toward extrasynaptic NMDAR signal-ling and the pathological emergence of Ca²⁺-permeable AMPARs (CP-AMPAR), ultimately driving synaptic failure and neuronal loss. Although numerous NMDAR and AMPAR-directed modulators have demonstrated neuroprotective efficacy in preclinical models, clinical translation has been lim-ited by inadequate spatial, kinetic, and subunit selectivity, as well as adverse effects arising from the disruption of physiological glutamatergic transmission. In this review, we synthesize the literature published between June 1990 and March 2025 to develop an integrative framework that links recep-tor localization, downstream Ca²⁺-dependent signalling, astrocytic regulation, mitochondrial dys-function, and disease progression across these disorders. By critically evaluating both successful and failed therapeutic strategies, we provide insight into evident research gaps in the field and the neces-sity of addressing them to develop precise multi-target approaches at both the genetic and cellular levels as next-generation therapeutics. Such an approach would be essential to move beyond indis-criminate receptor blockade strategies, which have repeatedly proven ineffective over the decades, and towards a future of durable neuroprotection.