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 protein in all striated muscles. Dystrophin protein loss disrupts the dystrophin-associated glycoprotein complex (DGC) and alters cellular mechanical and signaling functions causing membrane instability, necrosis, and progressive muscle wasting. Immune cell infiltration is a prominent feature of DMD pathophysiology and is strongly associated with disease severity. Currently, there is no curative treatment available for DMD. A logical therapeutic approach for DMD is to directly target the primary defect of DMD, sarcolemma instability, thereby preventing muscle membrane damage. First-in-class synthetic triblock 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. Creatine kinase (CK) is a well-established biomarker of DMD that reflects sarcolemma damage preceding fulminant muscle fiber necrosis. Serum CK levels have been shown to increase dramatically in dystrophin-deficient mdx mice but have not been fully characterized during the early postnatal growth period. Results here show, in the mdx mouse model of DMD, serum CK levels significantly increase compared to age-matched controls 15 days after birth and continue to increase dramatically over the neonatal period. Mass cytometry analysis of muscle-derived single cells at postnatal day six reveals significantly increased immune cells, predominantly non-monocyte-derived macrophages, in the dystrophin-deficient mdx skeletal muscle compared to the wild-type control. Strikingly, systemic delivery of P188 to neonatal mdx mice, starting postnatal day 1 or 2, prevents the serum CK increase and significantly prevents immune cell accumulation compared to saline-injected control mdx mice. These findings support the hypothesis that early intervention with first-in-class synthetic membrane stabilizers has the potential to mitigate muscle damage and blunt the inflammatory response characteristic of DMD disease pathology.