Laminin-α2-related muscular dystrophy (LAMA2-CMD) is a devastating neuromuscular disorder characterized by progressive muscle weakness from birth. As the most prevalent and fatal form of the congenital muscular dystrophies, LAMA2-CMD patients often die in their first decade of life. There currently is no cure or treatment for LAMA2-CMD. LAMA2-CMD is caused by a mutation in the LAMA2 gene resulting in the complete or partial loss of functional laminin-α2, a protein critical for the formation of the heterotrimers laminin-211/221. Laminin-111 is the predominant laminin isoform in embryonic skeletal muscle and is structurally and functionally similar to Laminin-211/221. In this study, we used digital spatial protein profiling using muscle from LAMA2-CMD patients and a mouse model. Our analysis revealed a multitude of differentially expressed proteins including those involved in cellular stress, survival, growth, and immune response from the muscle of LAMA2-CMD patients. Studies using the dyW-/- mouse model also showed downregulation of proteins associated with muscle growth, adhesion, and immune markers. Notably, treatment with recombinant human laminin-111 (rhLAM-111) rapidly restored levels of these proteins to wild-type levels. These results reveal altered cell signaling pathways in LAMA2-CMD muscle which contribute to the complex pathology observed with muscle disease progression. Our mouse model studies underscore the pivotal role that laminin plays as a key regulator in skeletal muscle cell signaling, and its role in promoting skeletal muscle growth, survival, and function. These findings support rhLAM-111 as a therapeutic intervention for ameliorating muscle disease progression in LAMA2-CMD patients and provide novel insights into critical pathways influenced by the presence of laminin-α1 or laminin-α2 in the myomatrix.