Heart failure carries a poor prognosis with few treatment options. While myocardial stem cell therapeutic trials have traditionally relied on intracoronary infusion or intramyocardial injection routes, these cell delivery methods are invasive and can introduce harmful scar tissue, arrhythmia, calcification, or microinfarction in the heart. Given that patients with heart failure are at an increased surgical risk, development of a non-invasive stem cell therapeutic approach is logistically appealing. Taking advantage of the trophic effects of bone marrow mesenchymal stem cells (MSCs) and using a hamster heart failure model, the present study demonstrates a novel non-invasive therapeutic regimen via direct delivery of MSCs into the skeletal muscle bed. Intramuscularly injected MSCs and MSC-conditioned medium each significantly improved ventricular function one month after MSC administration. MSCs at 4 million cells per animal increased fractional shortening by ~40%, enhanced capillary and myocyte nuclear density by ~30% and ~80%, attenuated apoptosis by ~60%, and reduced fibrosis by ~50%. Myocyte regeneration is evidenced by a ~2-fold increase in expression of cell cycle markers and ~13% reduction in mean myocyte diameter. Increased circulating levels of hepatocyte growth factor (HGF), leukemia inhibitory factor (LIF), and macrophage colony-stimulating factor (M-CSF) were associated with mobilization of c-kit⁺, CD31⁺, and CD133⁺ progenitor cells and subsequent increase in myocardial c-kit⁺ cells. Trophic effects of MSCs further activated expression of HGF, insulin-like growth factor-2 (IGF-2), and vascular endothelial growth factor (VEGF) in the myocardium. The work highlights a cardiac repair mechanism mediated by trophic cross-talks between the injected MSCs, bone marrow, and heart that can be explored for non-invasive stem cell therapy.