Background: Cardiomyopathy is a principal cause of morbidity and mortality in Duchenne muscular dystrophy (DMD). The development of therapeutics to treat cardiac complications is hampered by an incomplete understanding of the pathogenesis of dystrophin-deficient cardiac disease. Recently, we discovered a novel pathogenic mechanism of DMD in which Klotho (KL) is epigenetically silenced resulting in up to an 80% reduction of expression in skeletal muscle. KL is expressed as multiple isoforms from the same gene, including as a transmembrane protein and as a soluble form (sKL), produced by proteolytic cleavage, that can function as a hormone. KL works in cooperation with its co-factor fibroblast growth factor (FGF)23 to regulate mineral ion homeostasis. Mice lacking KL suffer from shortened lifespan, premature aging, and cardiac hypertrophy. Objective: To test the hypothesis that the expression of a systemic KL transgene in mdx mice reduces pathological cardiac remodeling and preserves function. Results: Our findings indicate that KL is not expressed in the wild-type or mdx heart. However, we do detect a sustained increase in FGF23 expression in the heart and circulation as pathology emerges in mdx mice. KL transgene expression in mdx mice had remarkable, ameliorating effects on cardiac remodeling resulting in a 38% reduction in cardiac myocyte size and a 63% reduction in collagen 1 accumulation. Our histo-morphological analyses were further supported by QPCR assays showing reduced expression of hypertrophic (Nppa and Myh7) and fibrogenic (Col1a2, Postn, and Timp2) transcripts. Finally, KL preserved cardiac function in mdx mice by attenuating deficits in stroke volume, ejection fraction, fractional shortening, and cardiac output. Conclusions: Our findings show that KL reduces dystrophic cardiomyopathy possibly by inhibiting the actions of FGF23 in the heart and that KL treatment could have therapeutic value by reducing pathology in both dystrophic skeletal and cardiac muscle.