Duchenne Muscular Dystrophy is a genetic muscle disease characterized by chronic inflammation and fibrosis, mediated by a pro-fibrotic macrophage population expressing pro-inflammatory markers. Our aim was to characterize cellular events leading to the alteration of macrophage properties, and to modulate macrophage inflammatory status using the gaseous mediator H2S. Using co-culture experiments, we first showed that myofibers derived from mdx mice strongly skewed the polarization of resting macrophages towards a pro-inflammatory phenotype. Treatment of mdx mice with NaHS, an H2S donor, reduced the number of pro-inflammatory macrophages in skeletal muscle, which was associated with a decreased number of nuclei per fiber, together with a reduced myofiber branching and fibrosis. Finally, we established the metabolic sensor AMPK as a critical NaHS target in muscle macrophages. These results identify an interplay between myofibers and macrophages where dystrophic myofibers contribute to the maintenance of a highly inflammatory environment sustaining a pro-inflammatory macrophage status, in turn favoring myofiber damage, myofiber branching and fibrosis establishment. They also identify H2S donors as a potential therapeutic strategy to improve dystrophic muscle phenotype by dampening chronic inflammation.