Neuroexcitotoxicity is one of the important pathogenic mechanisms of ischemic stroke and many neurodegenerative diseases. Nicotinamide adenine dinucleotide phosphate (NADPH) is an essential electron donor in all organisms, maintaining anabolic reactions and redox homeostasis. During neuroexcitotoxicity, NADPH mobilizes multiple defense mechanisms to reduce destructive pathological injury to neurons, including oxidative stress, hyperactivation of autophagic flux, mitochondrial dysfunction, and ferroptosis. This section summarizes and discusses the biological functions, regulatory mechanisms, and corresponding therapeutic intervention strategies of NADPH in neuroexcitotoxicity.