Background: The study was aimed to analyze the potential gene modules and hub genes of Duchenne muscular dystrophy (DMD) by weighted gene co-expression network analysis. Methods: Based on the muscular dystrophy tissue expression profiling microarray GSE13608 from gene expression omnibus, gene co-expression modules were analyzed using weighted gene co-expression network analysis, gene modules related to DMD were screened, gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses were performed, and signature genes in the modules were screened. The protein–protein interaction network was constructed through Cytoscape, and hub genes were identified. The expression of hub genes in DMD versus normal muscle tissue was calculated in GSE6011. Results: 12 co-expressed gene modules were identified, among which black module was significantly related to DMD. The characteristic genes in the module were enriched in the regulation of immune effector processes, immune response mediated by immunoglobulin, immune response mediated by B cells, etc. SERPING1, F13A1, C1S, C1R, and HLA-DPA1 were considered as hub genes in protein–protein interaction network. Analysis of GSE6011 shows that expression of SERPING1, F13A1, C1S, C1R, and HLA-DPA1 in tissues of DMD patients were higher than normal. Conclusion: SERPING1, F13A1, C1S, C1R, and HLA-DPA1 may participate in the development of DMD by regulating innate immunity and inflammation, and they are expected to be a potential biomarker and novel therapeutic targets for DMD.