The glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) share ligands and are critical for treatment of numerous forms of chronic inflammation and heart failure. In Duchenne muscular dystrophy (DMD), prednisone is standard-of-care and it acts as an agonist for both the GR and MR. There is a growing need to understand the mechanisms of GR/MR ligands and to dissect receptor-specific roles in dystrophic hearts to develop more selective treatments. Here, we dissect mechanisms of the GR in the etiology and treatment of muscular dystrophy. First, we produce and characterize a new tissue-specific double knockout mouse featuring knockout of the GR in skeletal muscle and heart. Knockout of the GR (mdx:mCK-GRnull) worsens mdx strength deficits, increases skeletal muscle mass, and increases inflammatory gene expression in muscle (IL-6, IL-1b, Ccl2), despite intact GR signaling in immune cells. GR knockout also disrupts the balance of GR/MR signaling to worsen heart phenotypes, leading to a 23% increase in mdx heart mass and dysregulation of cardiac gene expression (Ccl2, Acta2, Ptgds). Next, we perform a blinded preclinical trial of prednisolone in double knockouts versus mdx littermate controls. Importantly, we find prednisolone efficacy is completely ablated by tissue-specific GR deletion. Knockout prevents drug benefits to strength phenotypes, muscle mass and histopathology. Double knockout mice continue to show increased heart mass with prednisolone treatment, alongside disrupted drug responses in cardiac gene expression (IL-6, Klf15, Ptgds). Both genotypes show signs of classical prednisone side effects including growth stunting, glucose dysregulation and immunosuppression; this shows prednisone efficacy is separate from these systemic effects and, importantly, efficacy relies on GR expression directly within myofibers. Together, our data are consistent with a model where the GR acts directly within dystrophic myofibers to dampen disease severity and potentiate drug efficacy, while also protecting dystrophic hearts locally by balancing GR/MR signaling within cardiomyocytes.