Ischemic heart disease, represented by acute myocardial infarction (AMI), is the leading cause of death in the world. Although the survival rate after AMI has improved with the development of reperfusion therapy, there are still many patients with poor prognoses progressing to heart failure after AMI. Thus, it is essential to understand the pathogenesis after MI and explore a novel therapeutic target. Progranulin is a growth factor associated with wound healing and inflammation. We previously reported that administration of progranulin had the protective effects on cardiac injury after MI in animal models. However, the role of endogenous progranulin on cardiac remodeling after MI is still unelucidated. In this study, we evaluated the role of progranulin in the pathophysiology post-MI using in vivo MI model mice. The expression level and localization of progranulin in the heart of MI model mice were investigated using Western blotting and immunostaining. We also analyzed the cardiac remodeling and survival rate after MI in progranulin KO and WT mice. Progranulin expression significantly increased in the whole heart 3 and 7 days after MI. The localization of progranulin was observed at the infarct border area. Fibrosis area and heart weight/body weight ratio significantly increased in progranulin KO mice compared with WT mice after MI. The survival rate was significantly reduced in progranulin KO mice compared with WT mice. Thus, it is suggested that progranulin has a crucial role in the protection from heart failure after MI.