Myocardial ischemia/reperfusion (I/R) injury after the onset of acute myocardial infarction (AMI) can be life-threatening, and there is no effective strategy for therapeutic intervention. Here, we studied the potential of protectin D1 in protecting from I/R-induced cardiac damages and investigated the underlying mechanisms. An in vivo rat model of I/R after AMI induction was established through the ligation of the left anterior descending (LAD) artery to assess the cardiac functions and evaluate the protective effect of protectin D1. Protectin D1 protected against I/R-induced oxidative stress and inflammation in the rat model, improved the cardiac function, and reduced the infarct size in myocardial tissues. The beneficial effect of protectin D1 was associated with the up-regulation of miRNA-210 and the effects on PI3K/AKT signaling and HIF-1a expression. Together, our data suggest that protectin D1 could serve as a potential cardioprotective agent against I/R-associated cardiac defects.