Objective: To investigate the neuroprotective effects of sivelestat (SV) in a porcine cardiac arrest-resuscitation model while exploring its association with the NF-κB/NLRP3 pathway. Methods: Fifteen healthy male pigs were randomly assigned to the sham operation group (Sham, n=5), the cardiopulmonary resuscitation group (CPR, n=5), and the CPR with SV treatment group (CPR+SV, n=5). Cardiac arrest was induced by ventricular fibrillation for 9 minutes in the CPR and CPR+SV groups, followed by 6 minutes of cardiopulmonary resuscitation to establish the experimental model. To assess the potential protective effects of SV, five minutes after successful resuscitation, the CPR+SV group received SV at 10 mg/kg via femoral vein infusion for 1 hour using a micro-infusion pump. Blood samples were collected from the femoral vein at baseline and at 0.5, 1, 2, and 4 hours post-resuscitation for serum levels of neuron-specific enolase (NSE) and S100β protein, recognized as markers of brain injury, via ELISA. Neurological function was assessed 24 hours post-resuscitation using neurological deficit scores (NDS). The animals were euthanized 24 hours post-resuscitation, and left ventricular apical myocardial and frontal lobe cortex tissues were harvested. Brain tissue levels of inflammatory markers, IL-1β and IL-18, were analyzed using Western blotting. Western blot was used to evaluate the effect of SV in reducing the expression levels of NF-κB, NLRP3, cleaved caspase-1, and GSDMD, key markers of pyroptosis, in the brain tissues of pigs after CPR. Results: Post-resuscitation, the CPR and CPR+SV groups exhibited significantly higher serum levels of NSE and S100β and elevated NDS scores compared to the Sham group (all P<0.05). Nevertheless, the CPR+SV group showed significantly improved neurological scores and reduced levels of brain injury markers at all time points post-resuscitation versus the CPR group (P<0.05). At 24 hours post-resuscitation, IL-1β and IL-18 levels in the brain tissues of CPR and CPR+SV groups were markedly higher than those in the Sham group (P<0.05). Conversely, the levels of inflammatory factors in the CPR+SV group were significantly reduced compared to the CPR group (P<0.05). At 24 hours post-resuscitation, brain tissue expression of NF-κB, NLRP3, cleaved caspase-1, and GSDMD was markedly elevated in the CPR group (P<0.05). SV markedly suppressed the expression of these pyroptosis-associated proteins (P<0.05), highlighting its potential role in neuroprotective via inhibition of the NF-κB/NLRP3 pathway. Conclusion: SV effectively mitigates post-resuscitation brain injury and enhances neurological outcomes, likely through its regulatory effects on the NF-κB/NLRP3 pathway.