Chronic Obstructive Pulmonary Disease (COPD) is a major public health disease characterized by chronic inflammation and punctuated by worsening periods often triggered by viral infections, called exacerbations. Skeletal muscle dysfunction is a prevalent comorbidity, lacking effective treatment, and is often linked to exacerbations. The implication of both the chemokine receptor CXCR4 and its ligand CXCL12 has been suggested in COPD. Our goal was to study its implication in skeletal muscle dysfunction in a murine model of early COPD. C57BL/6 mice were exposed for ten weeks to cigarette smoke (CS) and intranasal instillations of poly-IC to mimick exacerbations. A conditional inactivation of CXCR4 was also generated via a tamoxifen-inducible Cre/Lox system in CS-exposed mice. Skeletal muscle function was assessed and skeletal muscle tissues were harvested for histological and proteomic analysis. CS-exposed mice displayed no evidence of decreased force or muscular atrophy compared to control mice, but their resistance to fatigue, assessed by the hanging test, was significantly decreased, and this was attenuated in the CXCR4-/- exposed group. Analysis of the soleus muscle showed a metabolic switch from oxidative to glycolytic myofibers in the exposed group, as well as a tendency to decreased capillarization, which were both reversed in the CXCR4-/- exposed mice. Proteomic and transcriptomic analysis showed a dysregulation in mitochondrial proteins as well as inflammation in the CS group. These results provide a framework to study the CXCL12/CXCR4 axis and implicated cells in COPD skeletal muscle dysfunction.