Duchenne Muscular Dystrophy (DMD) is a devastating progressive skeletal and cardiac myopathy, with cardiac failure as the leading cause of mortality. Fibrosis is one of the first clinical signs of DMD-associated cardiomyopathy indicating the presence of activated fibroblasts during early disease progression. However, the contribution of fibroblasts to the disease pathogenesis is incompletely understood. We have found that fibroblast growth factor 23 (FGF23) expression is greatly increased in dystrophic cardiac fibroblasts. Elevated FGF23 levels have been associated with high-risk for all-cause cardiovascular mortality and ventricular dilation in pediatric dilated cardiomyopathy patients. Here, we tested the hypothesis that cardiac fibroblast FGF23 promotes dystrophic cardiac remodeling and impaired function. We generated dystrophin-null mdx mice carrying a PDGFR⍺-Cre transgene and flox-Fgf23 alleles permitting conditional deletion of FGF23 from cardiac fibroblasts. Cardiac function and morphology were assessed by ultrasound at baseline and following isoproterenol (Iso) stress-induced cardiac injury (sub-q, 2 mg/kg/day, 10-days) in 3-months-old mdx/flox-Fgf23 (WT) and mdx/flox-Fgf23/Pdgfr⍺-Cre+ (Cre+) mice. Iso-stimulated injury increased cardiac Fgf23 mRNA expression 6.1-fold in mdx hearts compared to control. At baseline, no cardiac functional abnormalities were evident. However, following iso-injury, ultrasound revealed that reductions in ejection fraction (Cre+: 54.3 3.4% vs. WT: 44.1 3.7%) and fractional shortening (Cre+ 28.1 2.1% vs. WT: 22.0 2.0%) were attenuated in Cre+ mice compared to genotype controls. Additionally, stress-stimulated increases in left ventricular systolic (Cre+: 31.4 4.4 l vs. WT: 47.9 5.8 l) and diastolic volume (Cre+: 66.2 3.6 l vs. WT: 82.9 4.0 l) were diminished in Cre+ mice. Our results support two significant findings. First, that FGF23 is a pathogenic factor that regulates dystrophin-deficient cardiac remodeling and function in response to injury. Second, paracrine factors produced by cardiac fibroblasts regulate dystrophic cardiac remodeling and function.