Myocardial infarction (MI) is one of most common cardiovascular diseases, and ischemia/reperfusion (I/R) injury is one of the risk factors for severe myocardial injury and dysfunction, even leading to high mortality of myocardial infarction. Liraglutide, a novel glucagon-like peptide 1 (GLP-1) analogue, has been reported to reduce cardiac rupture and infarct size and improve cardiac function in normal and diabetic rodents, however, the mechanisms of liraglutide on cardiomyocytes is not clear. The current research was designed to investigate the hypothesis that liraglutide would protect cardiomyocytes through regulating homer1 expression under hypoxia/reoxygenation (H/R) condition. The results of the present study indicated liraglutide reduced hypoxia-reoxygenation induced cell death and attenuated intracellular calcium overload in H9C2 cardiomyocytes under H/R condition. Moreover, liraglutide significantly increased the Homer1 protein expression, and this protection might be related to Homer1-dependent regulation of endoplasmic reticulum (ER) calcium homeostasis. Taken together, liraglutide protects H9C2 cell against H/R induced cell injury, and this protective effect may inhibit intracellular calcium overload to some extent, through Homer1-dependent regulation of ER calcium homeostasis.