Ischemic stroke is a worldwide major cause of mortality and disability and has high costs in terms of health-related quality of life and expectancy as well as of social healthcare resources. In recent years, starting from the bidirectional relationship between autonomic nervous system (ANS) dysfunction and acute ischemic stroke (AIS), researchers have identified prognostic factors for risk stratification, prognosis of mid-term outcomes and response to recanalization therapy. In particular, the evaluation of the ANS function through the analysis of heart rate variability (HRV) appears to be a promising non-invasive and reliable tool for the management of patients with AIS. Furthermore, preclinical molecular studies on the pathophysiological mechanisms underlying the onset and progression of stroke damage have shown an extensive overlap with the activity of the vagus nerve. Evidence from the application of vagus nerve stimulation (VNS) on animal models of AIS and on patients with chronic ischemic stroke has highlighted the surprising therapeutic possibilities of neuromodulation. Preclinical molecular studies highlighted that the neuroprotective action of VNS results from anti-inflammatory, antioxidant and antiapoptotic mechanisms mediated by α7 nicotinic acetylcholine receptor. Given the proven safety of non-invasive VNS in the subacute phase, the ease of its use and its possible beneficial effect in hemorrhagic stroke as well, human studies with transcutaneous VNS should be less challenging than protocols that involve invasive VNS and could be the proof of concept that neuromodulation represents the very first therapeutic approach in the ultra-early management of stroke.