Myocardial ischemia/reperfusion (MI/R) injury leads to aggravated cardiac remodeling and heart failure. Previously, we reported that 2,5-dimethylelcelecoxib (DMC), a derivative of celecoxib without cyclooxygenase-2 inhibition, prevents cardiac remodeling in a non-ischemic cardiac fibrosis model. In this study, we examined whether DMC inhibited myocardial remodeling associated with MI/R injury. The left anterior descending coronary artery was ligatured for 0.5 hours and subsequently subjected to reperfusion for MI/R injury in male C57 BL/6 mice. Vehicle or DMC was administered orally (DMC: 150 mg/kg) immediately after awakening and followed by feeding (DMC: 1000 ppm). Echocardiographic evaluation showed significant improvement of left ventricular ejection fraction in the DMC-treated group compared to the Vehicle-treated group at 1-4 weeks after MI/R injury. In MI/R-injured hearts, protein expression of alpha-smooth muscle actin (myofibroblast marker) was significantly reduced by DMC treatment, as were mRNA expressions of fibronectin, connective tissue growth factor, and matrix metalloproteinase-9, 3 days after injury. Masson trichrome staining indicated that DMC significantly reduced cardiac fibrosis area 4 weeks after MI/R injury. This study revealed that DMC decreased myofibroblast appearance, and suppressed fibrosis and cardiac dysfunction associated with MI/R injury. DMC might be useful for preventing the development of heart failure associated with reperfusion therapy for acute myocardial infarction.