Background: Acute myocardial infarction is one of the leading causes of death worldwide. Myocardial ischemia reperfusion (MI/R) injury occurs immediately after the coronary reperfusion and aggravates myocardial ischemia. Whether the Wnt/β-Catenin pathway is involved in the protection against MI/R injury by DADLE has not been evaluated. Therefore, the present study aimed to investigate the protective effect of DADLE against MI/R injury in a mouse model and to further explore the association between DADLE and the Wnt/β-Catenin pathway. Methods: Forty-four mice were randomly allocated to four groups: Group Control (PBS Control), Group D 0.25 (DADLE 0.25 mg/kg), Group D 0.5 (DADLE 0.5 mg/kg), and Group Sham. In the control and DADLE groups, myocardial ischemia injury was induced by occluding the left anterior descending coronary artery (LAD) for 45 min. PBS and DADLE were administrated, respectively, 5 min before reperfusion. The sham group did not go through LAD occlusion. 24 h after reperfusion, functions of the left ventricle were assessed through echocardiography. Myocardial injury was evaluated using TTC double-staining and HE staining. Levels of myocardial enzymes, including CK-MB and LDH, in the serum were determined using ELISA kits. Expression of caspase-3, TCF4, Wnt3a, and β-Catenin was evaluated using the Western blot assay. Results: The infarct area was significantly smaller in the DADLE groups than in the control group (P < 0.01). The histopathology score and serum levels of myocardial enzymes were significantly lower in the DADLE groups than in the control group (P < 0.01). DADLE significantly improved functions of the left ventricle (P < 0.01), decreased expression of caspase-3 (P < 0.01), TCF4 (P < 0.01), Wnt3a (P < 0.05), and β-Catenin (P < 0.01) compared with PBS. Conclusions: The present study showed that DADLE protected the myocardium from MI/R through suppressing the expression of caspase-3, TCF4, Wnt3a, and β-Catenin and consequently improving functions of the left ventricle in I/R model mice. The TCF4/Wnt/β-Catenin signaling pathway might become a therapeutic target for MI/R treatment. [ABSTRACT FROM AUTHOR]