Myocardial extracellular matrix (ECM) is essential for proper cardiac function and structural integrity; thus, the disruption of ECM homeostasis is associated with several pathological processes. Female Wistar rats underwent surgical ovariectomy (OVX) or sham operation (SO) and were then divided into eight subgroups based on the type of diet (standard chow or high-triglyceride diet/HT) and exercise (with or without running). After 12 weeks, cardiac MMP-2 activity, tissue inhibitor of metalloproteinase-2, content of collagen type I, the level of nitrotyrosine (3-NT) and glutathione (GSH), and the ratio of infarct size were determined. Our results show that OVX and HT diet caused an excessive accumulation of collagen; however, this increase was not observed in the trained animals. Twelve weeks of exercise promoted elevation in the levels of 3-NT and GSH and similarly an increase in MMP-2 activity of both SO and OVX animals. The high infarct-size ratio caused by OVX and HT diet was mitigated by physical exercise. Our findings demonstrate that ovarian estrogen loss and HT diet caused collagen accumulation and increased ratio of the infarct size. However, exercise-induced cardiac remodeling serves as a compensatory mechanism by enhancing MMP-2 activity and reducing fibrosis, thus minimizing the ischemia/reperfusion injury.