Cardiomyopathy is a leading cause of mortality in patients with Duchenne muscular dystrophy (DMD); however, the precise molecular basis for heart failure is incompletely understood. We have shown that dystrophin-deficient mdx mice have increased cardiac and systemic Fibroblast growth factor (FGF23) expression. FGF23 regulates phosphate mineral metabolism through its endocrine actions on the kidney, but chronic elevations in FGF23 are maladaptive and positively associated with greater risk of cardiovascular events. FGF23 induces cardiac remodeling by binding to Fibroblast growth factor receptor 4 (FGFR4) on cardiac myocytes. Here, we tested the effect of FGFR4 activation on dystrophin-deficient cardiac pathology and function. We generated dystrophin-null mice carrying a gain-of-function knock-in mutation of FGFR4, replacing a neutral glycine with charged arginine residue at codon 385. Increased FGFR4 activity had no effect on body mass, %fat mass or %lean mass. Left ventricular function was analyzed by transthoracic 2D-ultrasound. At 12-13 months of age, left ventricular ejection fraction (LVEF) was reduced in mdx mice (46.9±1.9%) compared to wild-type (55.7±0.63%); however, LVEF was preserved in mdx-FGFR4Arg385 (51.76±1.42%). Similarly, FGFR4 activity in mdx-FGFR4Arg385 mice (26.1±0.89%) rescued deficits in fractional shortening in mdx mice (23.2±1.15% vs. wild-type: 28.7±0.40%). In mdx-FGFR4Arg385 mice, we observed elevated LV mass (118±3.3 mg vs. mdx: 105.2±3.37 mg) marked by increased posterior wall myocardial thickness (LVPW;d 1.07±0.03 mm, vs. mdx: 0.91±0.03 mm and LVPW;s 1.37±0.03 mm vs. mdx: 1.15±0.04 mm) compared to mdx mice. Our echocardiography data demonstrates that constitutively increased FGFR4 activity improved systolic function and promotes cardiac hypertrophy in mdx mice.