Vagus nerve stimulation (VNS) can promote neurofunctional recovery following cerebral ischemic stroke (CIS), but the underlying mechanism remains unclear. PANoptosis, a novel form of inflammatory programmed cell death, may play a role in the progression of CIS. Our previous studies have indicated that Sirt1 exerts neuroprotection against CIS by modulating various programmed cell death pathways. It needs to be clarified whether and how VNS regulates PANoptosis through Sirt1, thereby affecting the recovery of CIS. This study aims to clarify the role of VNS in modulating neuronal PANoptosis following CIS, and elucidate its underlying mechanisms. Models of middle cerebral artery occlusion/reperfusion (MCAO/R) in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) in primary neurons were established to assess the occurrence of neuronal PANoptosis following CIS. Circulating Sirt1 levels were measured in two independent cohorts of acute ischemic stroke (AIS) patients. VNS was administered to activate Sirt1, and its effects on PANoptosis and neurological recovery were evaluated. We found that neuronal PANoptosis was induced following CIS, which was reversed via VNS intervention. Sirt1 levels in serum of AIS patients were significantly increased, and positively correlated with infarct volume and National Institutes of Health Stroke Scale scores. In contrast, Sirt1 was downregulated in brain tissue from rodent models and AIS patients. This discrepancy in expression levels can be attributed to the increased generation of Sirt1 by peripheral macrophages. VNS upregulated Sirt1 expression, while the Sirt1 inhibitor EX527 negated the effects of VNS on PANoptosis, infarct volume, and neurofunctional recovery. These findings indicate that VNS may inhibit PANoptosis and promote neurofunctional recovery following CIS in a Sirt1-dependent manner, which may be a new potential target for stroke therapy. Sirt1 may also serve as a blood biomarker for patient stratification with independent prognostic value in AIS patients.