Diabetic cardiomyopathy increases the risk of heart failure independent of coronary artery disease and hypertension. Phloretin (PHL) shows anti-inflammatory effects in macrophages. In this study, we explored the protective effects of PHL on high glucose (HG)-induced injury in diabetic cardiomyopathy in vivo and in vitro. Using streptozotocin-induced diabetic mouse model and incubating cardiac cells line under a HG environment, PHL were evaluated of the activities of anti-inflammation and anti-fibrosis. In the study, PHL treatment ameliorated cardiomyocyte inflammation injury, and reduced fibrosis in vivo and in vitro. PHL also improved cardiac biochemical criterions after 8 weeks of induction of diabetes in C57BL/6 mice. Molecular docking results indicated that silent information regulator 2 homolog 1 (SIRT1) bound to PHL directly and that SIRT1 expression was upregulated in the PHL-treated group in HG-induced H9C2 cells. Protective effect of PHL was been eliminated in silence SIRT1 H9C2 cells. Taken together, these results suggested that PHL suppressed HG-induced cardiomyocyte injury via restoring SIRT1 expression.