Intestinal　ischemia-reperfusion　(I/R)　injury　is　a　life-threatening　vascular　emergency　and　has　long　been　a　disturbing　problem　for　surgeons.　Oxidative　stress　is　considered　a　vital　factor　in　I/R　injury.　Metformin　has　antioxidative　properties　and　protects　against　I/R　injury.　The　present　study　aimed　to　investigate　whether　Metformin　protects　against　intestinal　I/R　injury　and　reveal　the　protective　mechanism　of　Metformin.　I/R　injury　was　induced　in　mice　by　temporary　superior　mesenteric　artery　occlusion,　and　Caco-2　cells　were　subjected　to　OGD/R　to　establish　an　in　vitro　model.　Different　doses　of　Metformin　were　administered　in　vivo　and　in　vitro.　We　found　that　I/R　injury　led　to　intestinal　barrier　disruption　and　cell　death　by　examining　histopathological　results　and　the　intestinal　barrier　index,　including　TER,　tight　junction　proteins　and　serum　biomarkers.　We　confirmed　the　existence　of　pyroptosis　in　intestinal　I/R　injury.　Moreover,　we　confirmed　the　role　of　pyroptosis　in　intestinal　I/R　injury　by　silencing　the　gasdermin　D　(GSDMD).　Then,　we　confirmed　that　Metformin　treatment　protected　barrier　function　against　intestinal　I/R　injury　and　reduced　oxidative　stress　and　the　inflammatory　response.　Importantly,　Metformin　reduced　pyroptosis-related　proteins,　including　NLRP3,　cleaved　caspase-1,　and　the　N-terminus　of　GSDMD.　Knocking　down　the　GSDMD　could　reversed　the　protective　effects　of　Metformin,　which　showed　pyroptosis　was　one　of　the　major　cell　death　pathways　controlled　by　Metformin　treatment　in　setting　of　intestinal　I/R　injury.　We　also　discovered　that　Metformin　suppressed　the　expression　of　TXNIP　and　the　interaction　between　TXNIP　and　NLRP3.　We　performed　siRNA　knockdown　and　found　that　the　protective　effects　were　abolished,　which　further　confirmed　our　findings.　In　conclusion,　we　believe　that　Metformin　protects　against　intestinal　I/R　injury　in　a　TXNIP-NLRP3-GSDMD-dependent　manner.