JAK2/STAT3 is a cardio-protective, pro-inflammation pathway, the function of which in cardiomyopathy caused by diabetic (DCM) is currently unknown. Here we explore the role of the JAK2/STAT3 pathway in DCM employing different time courses and a type 2 DM (T2DM) rat model. We examined the interactions of metformin and sitagliptin treatment with the JAK2/STAT3 pathway and cardiac remodeling. A T2DM rat model was induced by high fat diet/streptozotocin (HFD/STZ) and treated with metformin, sitagliptin (10 mg/d or 20 mg/d) or a placebo. Cell inflammation markers, cardiac remodeling and cardiomyocyte apoptosis were evaluated. We observed an activated inflammation reaction as well as activation of the JAK2/STAT3 thought-out the experiment in the simple HFD group only in the early stage of the disease (until week 9). JAK2/STAT3 activity showed a phasic peculiarity as increased inflammation was observed in prolongation of the DCM accompanied with an accelerated cardiac dysfunction but reduced phosphorylation of myocardial STAT3. Moreover, in the metformin but not the sitagliptin treated group, JAK2/ STAT3 activation was associated with having better improved cardiac remolding and reduced myocardial apoptosis. In vitro studies further validated that metformin could activate JAK2/STAT3 pathway and alleviate apoptosis of NRCMs under hyperglycemia incubation. The phasic feature of JAK2/STAT3 pathway activation may participate in the pathophysiological development of DCM. The superior cardio-protective effect of metformin over sitagliptin treatment may partly account for the differences we observed in JAK2/STAT3 activation, indicating that measuring JAK2/ STAT3 pathway coupled with metformin treatment may give insight into a more promising DM treatment.