Pentoxifylline (PTX) protects from many cardiovascular complications. It plays a critical role in stem cell proliferation and differentiation. Here, the effect of PTX administration on cardiac ischemia and dysfunction was explored. PTX in 3 doses (20, 30, and 40 mg/kg), was administered in vivo 5 min before a 45 min occlusion of the left anterior descending artery, followed by a 120 min reperfusion in male Wistar rats. The left ventricular end-diastolic pressure and dP/dt_max were assessed. Blood and cardiac tissue samples were collected for measuring the levels of cardiac enzymes and the expression of lncRNA-00654-miR-133a-SOX5. Samples of left ventricles were collected and processed for light microscopic, immunohistochemical staining for c-kit (a marker for cardiac progenitor cells) and transmission electron microscopic examination. PTX administration showed improvements in cardiac function tests, enzymes, and myocytes. Microscopic features showed minimal cardiac edema, hemorrhage, cellular inflammatory infiltration and fibrosis in addition to increased c-kit + cells in cardiac tissue samples. Notably, this treatment also produced a dose-dependent decrease in lncRNA-00654 with an increase in SOX5 mRNA and miRNA-133a-3p expressions. In conclusion, PTX has the potential to alleviate cardiac injury and increase the number of c-kit + cells following ischemia-reperfusion in the rat model via modulation of lncRNA-00654 and miR-133a-SOX5 mRNA expressions.