<p>Lactate, a key glycolytic metabolite, is integral to the maintenance of central nervous system (CNS) homeostasis. Beyond serving as an energy substrate via the astrocyte–neuron lactate shuttle, lactate modulates microglial activation, promotes oligodendrocyte-driven myelination, and supports axonal development and synaptic plasticity. Recent discoveries have revealed that lactate can be enzymatically converted to lactyl-CoA, initiating protein lactylation—a novel epigenetic modification that directly regulates gene transcription and protein function. These interrelated processes shape cellular metabolism, immune regulation, and neural plasticity, forming an elaborate regulatory network essential for CNS function and homeostasis. Accumulating evidence suggests disturbances in lactate metabolism and aberrant lactylation in the pathogenesis of neuropsychiatric disorders, including schizophrenia and depression. Elucidating the dual role of lactate as both a metabolic substrate and an epigenetic modifier offers a novel perspective on the molecular mechanisms underlying CNS physiology and pathology, and suggests promising metabolic-epigenetic therapeutic strategies for neuropsychiatric disorders.</p>