Myocardial infarction (MI) has emerged as the primary cause of global mortality. Managing blood sugar levels could play a vital role in the treatment of MI. Dapagliflozin (DPG), a commonly used hypoglycemic drug, has demonstrated efficacy in treating heart failure. However, the impact of DPG on MI remains unclear. We aimed to investigate the effects and mechanisms of DPG in relation to MI. DPG administration alleviated MI-induced cardiac dysfunction and myocardial fibrosis. We also found that DPG administration mitigated cardiomyocyte apoptosis through TUNEL staining. CD31 and α-Sma staining revealed that DPG promotes post-MI angiogenesis in mice. In vitro, using scratch assays, transwell assays, and tube formation assays, we discovered that DPG enhanced HUVEC proliferation capacity. Mechanistically, DPG promoted the expression of extracellular matrix genes and mitochondrial function-related genes. Additionally, molecular docking identified the interaction between DPG and PXR, which activated PXR and recruited it to the promoters of Pgam2 and Tcap, promoting their expressions, thus facilitating angiogenesis and post-MI heart repair. DPG promotes angiogenesis by activating PXR, thereby alleviating cardiac dysfunction and fibrosis after myocardial infarction. This study provides new strategies and targets for the treatment of ischemic disease. Display omitted •Dapagliflozin exerts cardioprotective effects in myocardial infarction.•Dapagliflozin promotes endothelial cell proliferation and migration.•Cardioprotective effects of Dapagliflozin is via interacting and activating PXR.•PXR upregulates genes related to ECM and mitochondrial function to repair infarcted hearts.