Mdx mice show a milder phenotype than Duchenne patients despite bearing an analogous genetic defect. Our aim was to sort out genes, differentially expressed during the evolution of mdx mice disease, which could explain the phenotypic differences between mdx mice and humans. Based on previous mdx longitudinal pathological studies, genome-wide microarray-based gene expression analysis in mdx and control mice were carried out at 3 weeks, 1.5 and 3 months of life. Candidate genes were selected by comparing differential expression (1.5-fold) in: 1) mdx vs. controls at each point in time, and 2) mdx mice and 3) control mice among the three points in time. The first analysis showed a strong up-regulation of the majority (96%) of the inflammation-related genes and in more than 75% of genes related to cell adhesion, muscle structure/regeneration and extracellular matrix remodeling during mdx disease evolution. Lgals3, Postn, Ctss and Sln genes showed the strongest variations. The analysis performed among the different points in time in both mdx and control mice showed their temporal gene expression evolution and demonstrated significant changes in Ecm1, Spon1, Thbs1, Csrp3, Myo10, Pde4b and Adamts-5 expression exclusively during the mdx mice lifespan. Further, RT-PCR analysis of Postn, Sln, Ctss, Thbs1, Ecm1 and Adamts-5 expression at 3 weeks, 1.5, 3, 6 and 9 months, confirmed microarray data and demonstrated variations beyond 3 months of age. A high-confidence functional network analysis of selected genes demonstrated a strong relationship between them and showed two main sub-networks, having Dmd-Utrn-Myo10 and Adamts5-Thbs1-Spon1-Postn as principal nodes, which are functionally linked to Abca1, Actn4, Crebbp, Csrp3, Lama1, Lama3, Mical2, Mical3, Myf6, Pxn and Sparc genes. This study presents a subset of candidate genes that may participate in the decline of muscle necrosis in mdx mice, and therefore could be considered as potential therapeutic targets for Duchenne patients.