Vagus nerve stimulation (VNS) has emerged as a promising neuromodulatory therapy for ischemic stroke that uses multifaceted mechanisms to address acute injury and chronic recovery. This review synthesizes evidence from preclinical and clinical studies, highlighting three neuroprotective mechanisms of VNS: (1) hemodynamic optimization through cholinergic-mediated vasodilation and neurovascular coupling enhancement, (2) suppression of proinflammatory cascades via the cholinergic anti-inflammatory pathway (e.g., >60% TNF-α reduction in animal models), and (3) facilitation of neuroplasticity via brain-derived neurotrophic factor (BDNF) upregulation and reorganization of neural networks. Preclinical studies have demonstrated robust efficacy, including 38% infarct reduction in rodent models, whereas clinical trials have found heterogeneous outcomes, with 65%–82% of patients achieving functional improvement, underscoring the need for personalized protocols. Technological advancements are pivotal: noninvasive transcutaneous VNS (tVNS) offers safer alternatives to comparable acute-phase efficacy, and closed-loop systems integrating electroencephalography (EEG), functional magnetic resonance imaging (fMRI), and biomarker feedback reduce adverse effects by 37% through adaptive parameter optimization. However, translational challenges persist, including interspecies pathophysiological disparities, trial design heterogeneity, and long-term safety concerns (e.g., 28%–33% incidence of neural adaptation in chronic invasive VNS). Future directions emphasize humanized stroke models, multimodal data integration, and cost-effective tVNS deployment to improve accessibility. This review delineates a roadmap for VNS clinical translation by bridging mechanistic insights with engineering innovations, positioning VHS as a transformative adjunct therapy in precision stroke rehabilitation.