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Its therapeutic potential has expanded dramatically, with growing evidence supporting its efficacy across a wide spectrum of neurological, psychiatric, cardiovascular, immunological, metabolic, and gastrointestinal disorders. Despite this progress, the field has lacked a comprehensive synthesis that unifies mechanistic insights with translational applications across organ systems. This review addresses that gap by systematically integrating current knowledge in the multifactorial mechanisms through which VNS modulates central and peripheral functions, including neuromodulator release, synaptic plasticity, autonomic regulation, neuroimmune control, and endocrine integration. In addition, this review identifies key limitations of VNS, including biological heterogeneity, technical constraints, and methodological variability, and proposes future innovations such as selective fiber targeting, closed\u2010loop systems, and artificial intelligence\u2010guided personalization. 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