Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease caused by a mutation in the dystrophin gene, resulting in a complete loss of dystrophin from the striated muscles. Dystrophin deficiency disrupts the dystrophin-glycoprotein complex (DGC) and alters muscle mechanical and signaling functions, causing membrane instability, necrosis, and progressive muscle wasting. Immune cell infiltration and inflammatory activation are prominent early features of DMD pathophysiology associated with disease severity. Currently, there is no curative treatment available for DMD. One therapeutic approach for DMD is to directly target the primary defect of DMD, sarcolemma instability, to prevent contraction-induced muscle membrane damage. First-in-class synthetic linear copolymer, poloxamer 188 (P188), is a muscle membrane interfacing and stabilizing molecule that protects dystrophic myocardium and skeletal muscle from acute stress-induced injury in vivo. We investigated the dystrophin-deficient skeletal muscle before the necrosis onset on postnatal day 20 (P20) in the mdx mouse model. Mass cytometry analysis of muscle-derived single cells at P6 revealed a substantial accumulation of immune cells, predominantly macrophages, in the dystrophin-deficient mdx skeletal muscle compared to the wild-type control. Systemic delivery of P188 to neonatal mdx mice, starting at P1/P2, protected the muscle architecture and blunted the immune cell accumulation compared to saline-injected control mdx mice. These findings support the hypothesis that early intervention with membrane stabilizers mitigates muscle damage and blunts the inflammatory response characteristic of DMD disease pathology.