Objective  To explore the ameliorative effect of chelated zinc on neuronal pyroptosis during the acute phase of cerebral ischemia in mice. Methods  Thirty adult male Kunming mice (25-30 g) were randomly divided into three groups according to the randomized controlled principle, sham operation group (sham), middle cerebral artery occlusion (MCAO) reperfusion 3 days group (MCAO), and zinc chelation Tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN) group, with 10 mice in each group. Mice in each group were anesthetized by inhalation, and MCAO model was established by the suture-occlusion method. Mice in each group were subjected to 1 hour of ischemia followed by 3 days of reperfusion. Mice in the TPEN group were intraperitoneally injected with the zinc ion chelator TPEN at a dose of 10 mg/kg immediately after reperfusion, while mice in the sham group only underwent blunt separation of blood vessels. Neurological function scoring, 2,3,5-triphenyltetrazolium chloride (TTC) staining, and laser speckle imaging were used to evaluate the protective effect of zinc chelation on cerebral injury in mice. Transmission electron microscopy, immunofluorescent staining, zinc probe, and Western blotting were performed to observe the improvement effect of zinc chelation on neuronal pyroptosis after cerebral injury in mice. Transcriptome sequencing combined with Gene Ontology (GO) enrichment analysis, immunofluorescence co-staining, and Western blotting were used to detect the expression levels of absent in melanoma 2 (AIM2), apoptosis-associated speck-like protein containing a CARD (ASC), Caspase-1, cleaved-Caspase-1, and gasdermin (GSDM) family proteins GSDMD-N proteins after zinc chelation intervention. Results  Zinc chelation improved the neurological function scores of mice (P<0.05), reduced the cerebral infarct volume (P<0.01), and restored the cerebral blood perfusion (P<0.001). Immunofluorescence co-staining results showed that compared with the model group, zinc chelation reduced intracellular zinc ion accumulation in neurons, decreased the number of neuronal deaths in the ischemic hemisphere, and lowered the content of free zinc ions. Transmission electron microscopy results revealed a significant reduction in pyroptotic bodies in the cerebral cortex of mice in the zinc chelation group compared with the model group. Transcriptome sequencing with GO enrichment analysis indicated that inflammation and massive pyroptosis erupted on 3 days after cerebral ischemia. Western blotting and immunofluorescence results demonstrated that TPEN treatment reduced the expression of AIM2 inflammasome proteins induced by cerebral ischemic injury (P<0.05). Conclusion  Chelated zinc exerts a neuroprotection against neuronal pyroptosis in mice after acute cerebral ischemia.