The standard-of-care for Duchenne Muscular Dystrophy (DMD) patients is glucocorticoid treatment, which improves skeletal muscle pathology in part by dampening chronic inflammation. Despite decades of use, severe side effects are associated with long-term glucocorticoid treatment, necessitating the use of safer immunomodulators. Spironolactone, a mineralocorticoid receptor (MR) antagonist exhibiting safety and efficacy for cardiovascular diseases, slows the development of cardiomyopathy in DMD patients and skeletal muscle pathology in dystrophic mice. In addition to lowering cardiac load by reducing blood pressure, inhibition of MR signaling diminishes pathology in other diseases by modulating inflammation. To determine if spironolactone treatment affects inflammation in dystrophic skeletal muscles, we treated the mdx mouse model of DMD with spironolactone during peak skeletal muscle necrosis and assessed inflammation and pathology. Littermate mdx mice were also treated in parallel with the glucocorticoid prednisolone to compare effects between these 2 drugs. Both drugs reduced cytokine signaling in mdx quadriceps while prednisolone treatment increased cytokine signaling in diaphragms, suggesting corticosteroids affect respiratory muscles differently than limb muscles. Myeloid cell populations quantified in both treatment groups with flow cytometry were unchanged in both muscle types. Whole-transcriptome RNA sequencing (RNA-Seq) of mdx quadriceps myeloid cells following in vivo treatment with spironolactone, prednisolone, or vehicle demonstrated distinct transcriptional signatures for each drug. Spironolactone primarily repressed gene expression pathways underlying inflammation and fibrosis. Prednisolone both activated and repressed hundreds of genes, affecting pathways implicated in reducing inflammation, but in contrast, increased expression of highly expressed fibrotic genes in myeloid cells. Aligned with the beneficial gene expression change in myeloid cells, diaphragm fibrosis was reduced after 1 week of spironolactone treatment in mdx mice. Spironolactone improves cardiac outcomes and skeletal muscle force, reduces muscle damage, and has anti-inflammatory properties. These beneficial effects support the consideration of spironolactone as an alternative to long-term glucocorticoids in muscular dystrophies.