Diabetic cardiomyopathy is characterized by structural and functional alterations to the heart including inflammation, fibrosis, and muscle stiffness. These alterations can ultimately lead to dysfunction in the left ventricle (LV). Bone marrow-derived mesenchymal stromal cells (MSCs) have many potential cardiac-aiding properties with demonstrated pro-angiogenic, anti-fibrotic, and general immunomodulatory effects. This study focuses on characterizing the ability of MSCs to reduce cardiomyopathic alterations in a mouse model for human type 2 diabetes mellitus. Twenty-week old db/db and control mice were administered CD362+, CD362−, and wild type MSCs intravenously. After four weeks, cardiomyocyte passive force (Fpassive) was assessed as a measure of stiffness. Using Aurora’s Permeabilized Myocyte Test System (1600A), it was found that all three MSCs had restorative effect on previously elevated Fpassive in db/db cardiomyocytes, with the effect of CD362+ being the least pronounced. Similarly, all three MSCs reestablished titin phosphorylation-regulating nitric oxide (NO) and cGMP levels to those seen in control mice, with CD362+ having the smallest effect. Arteriole density was then assessed to evaluate the pro-angiogenic properties of MSCs. CD362- and wild type were most effective in increasing arteriole density in db/db mice. Lastly, due to their marked influence on the progression of heart failure, a splenic cell analysis was conducted. Diabetic mice showed higher percentages of splenic apoptotic Tregs, lower amounts anti-inflammatory cells, and increased splenic pro-inflammatory cells. Application of all MSCs resulted in lower percentages of apoptotic Tregs compared to control mice. Treatment with CD362+ and wild type MSCs also resulted in increased anti-inflammatory splenic cells, whereas treatment with CD362- MSCs was most effective at decreasing pro-inflammatory cells. Overall, this study shows that the application of MSCs can reduce cardiomyocyte stiffness, restore NO and cGMP levels, and increase arteriole densities in diabetic mice, although CD362+ MSC were less effective.