Rationale: Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disease lacking effective treatment. Focusing on the early phase of COPD should help to discover disease modifying therapies. Objectives: In this study, we aimed at building a mouse model of early COPD and used it to study the role of the CXCL12-CXCR4 axis in both human and mouse early COPD. Methods: Blood and lung tissue were obtained from both COPD patients and mice exposed to cigarette smoke (CS) for 10 weeks and intranasal instillations of polyinosinic?polycytidylic?acid (poly(I:C)) to mimic exacerbations for 5 weeks. Measurements and Main Results: Exposed mice presented mild airway obstruction, peri-bronchial fibrosis and right heart remodeling. The level of CXCR4 expressing cells was increased in the blood of exposed mice, as well as in the blood of patients with mild COPD. Lung CXCL12 expression was higher both in exposed mice and COPD patients. The densities of fibrocytes expressing CXCR4 were increased in the blood and in the bronchial submucosa of exposed mice. Conditional inactivation of CXCR4 at adult stage as well as pharmacological inhibition of CXCR4 with plerixafor injections improved lung function and inflammation and protected against CS and poly-(I:C)-induced airway and cardiac remodeling. CXCR4-/- and plerixafor-treated mice also had reduced levels of CXCR4-expressing circulating cells and a lower density of peri-bronchial fibrocytes. Conclusions: We demonstrated that targeting CXCR4 has beneficial effects in an animal model of early COPD, and provide a framework to translate preclinical findings to clinical settings within a drug repurposing approach.