This review discusses the molecular mechanisms of excitotoxicity and its relevance to the pathogenesis of neurodegenerative diseases. Excitotoxicity, characterized by excessive activation of glutamate receptors, leads to detrimental outcomes such as impaired calcium buffering, generation of free radicals, mitochondrial permeability transition, and secondary excitotoxicity. Recent studies suggest that excitotoxicity may be a common pathway in various neurodegenerative diseases with distinct genetic etiologies. The review covers the involvement of ionotropic and metabotropic glutamate receptors, the role of ions (Na⁺, Cl⁻, Ca²⁺), oxidative stress, and mitochondrial-mediated apoptosis and autophagy in excitotoxicity. Specific neurodegenerative diseases, including Huntington's disease, Alzheimer's disease, and Parkinson's disease, are discussed in detail, highlighting the specific mechanisms of excitotoxicity and potential therapeutic targets. Understanding these mechanisms is crucial for developing effective treatments for neurodegenerative diseases.This review discusses the molecular mechanisms of excitotoxicity and its relevance to the pathogenesis of neurodegenerative diseases. Excitotoxicity, characterized by excessive activation of glutamate receptors, leads to detrimental outcomes such as impaired calcium buffering, generation of free radicals, mitochondrial permeability transition, and secondary excitotoxicity. Recent studies suggest that excitotoxicity may be a common pathway in various neurodegenerative diseases with distinct genetic etiologies. The review covers the involvement of ionotropic and metabotropic glutamate receptors, the role of ions (Na⁺, Cl⁻, Ca²⁺), oxidative stress, and mitochondrial-mediated apoptosis and autophagy in excitotoxicity. Specific neurodegenerative diseases, including Huntington's disease, Alzheimer's disease, and Parkinson's disease, are discussed in detail, highlighting the specific mechanisms of excitotoxicity and potential therapeutic targets. Understanding these mechanisms is crucial for developing effective treatments for neurodegenerative diseases.