Duchenne muscular dystrophy (DMD) is an X-linked myodegenerative disease associated with voluntary muscle weakness, respiratory insufficiency, and heart failure. Although the root cause of DMD is loss-of-function mutations in the Dmd gene, chronic inflammation drives disease progression. The cGAS-STING pathway is a critical component of the innate immune response to infection and cell stress. Chronic activation underlies human autoimmune diseases and aging, but this pathway has not been implicated in DMD. TY1, a synthetic non-coding RNA exomer, with disease-modifying bioactivity in mice with DMD works by up-regulating the DNA exonuclease, TREX1—a scavenger of cytosolic DNA upstream of cGAS-STING. Compared to healthy controls, macrophages from DMD patients and mdx mice have high levels of cytosolic DNA and low levels of TREX1. Such levels of cytosolic DNA are sufficient to activate cGAS and generate the cyclic dinucleotide, 2’3’-cGAMP in macrophages. Within macrophages, 2’3’-cGAMP activates STING and up-regulates pro-inflammatory gene expression. Macrophages can also secrete 2’3’-cGAMP, serving as a paracrine mediator of inflammation. When taken up by skeletal muscle myoblasts, 2’3’-cGAMP activates STING, suppresses proliferation, and blocks myotube formation—presumably leading to the broad regenerative defects observed in DMD skeletal muscle. Western blot and ELISA verified cGAS-STING to be active in mdx mouse skeletal muscle. In cell culture, TY1 boosted TREX1 levels, lowered cytosolic DNA, and lowered 2’3’-cGAMP production and secretion. When administered to mdx mice, TY1 suppressed cGAS-STING activation in skeletal muscle and boosted the numbers of Pax7+ myogenic precursors, MyoD+ myoblasts, and MYH8+ myofibers. These data provide compelling evidence that cGAS-STING is pathologically active in DMD. The previously unrecognized role of cGAS-STING in DMD now opens new opportunities for therapeutic intervention.