OBJECTIVES: Traumatic brain injury (TBI) affects millions annually and is a leading contributor to disability and mortality. The condition is marked by oxidative stress, inflammation, and pyroptosis, which play significant roles in neuronal impairment and functional deficits. Recent findings suggest that vagus nerve stimulation (VNS) provides neuroprotective effects in TBI, though the underlying mechanisms remain unclear. This study aims to determine in an animal model whether VNS enhances neural functional recovery post-TBI by inhibiting pyroptosis via the Orexin-A (OX-A)/NLRP3/Caspase-1/GSDMD signaling pathway, the role of OX-A was addressed via administration of the OX-A receptor antagonist SB334867. METHODS: Four groups of Sprague Dawley rats were randomly assigned: Sham group, TBI group, TBI + VNS group, and TBI + VNS + SB334867 group. A modified Feeney's method was utilized to induce TBI, followed by VNS administration. Neurological functions post-TBI were assessed using the modified neurological severity scale (mNSS) and morris water maze (MWM). Furthermore, a variety of techniques, including electron microscopy, Nissl staining, immunofluorescence, and quantitative polymerase chain reaction (qPCR), were employed to examine brain tissue damage, neuroinflammation, pyroptosis, and signaling pathway proteins. RESULTS: The findings revealed that VNS significantly enhanced neurological function, as indicated by lower mNSS scores and improved performance in the MWM test, suggesting a marked recovery in TBI-affected rats. Regarding tissue damage, VNS-treated rats displayed reduced brain injury, evidenced by enhanced mitochondrial integrity and diminished neuronal degeneration. Additionally, VNS reduced neuroinflammation, demonstrated by lower levels of IL-6, IL-1β, and TNF-α in the brain tissue of the TBI + VNS group as compared to the TBI group. Crucially, VNS inhibited pyroptosis by decreasing the expression levels of NLRP3, Caspase-1, ASC, and GSDMD in brain tissues. The introduction of the OX-A receptor antagonist SB334867 counteracted these protective effects, implying that VNS predominantly promotes neuroprotection via the OX-A pathway. CONCLUSIONS: VNS may alleviate neurological deficits and avert brain injury following TBI by attenuating neuroinflammation and pyroptosis, likely through the OX-A/NLRP3/Caspase-1/GSDMD signaling pathway, underscoring the pivotal role of OX-A in VNS-induced neuroprotection. Consequently, VNS represents a promising therapeutic strategy for TBI, providing a novel approach to reduce inflammation and pyroptosis.