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Background and objective: Chronic obstructive pulmonary disease (COPD) is a devastating disease commonly caused by cigarette smoke (CS) exposure that drives tissue injury by persistently recruiting myeloid cells into the lungs. A significant portion of COPD patients also present with overlapping asthma pathology including eosinophilic inflammation. The βc cytokine family includes granulocyte monocyte‐colony‐stimulating factor, IL‐5 and IL‐3 that signal through their common receptor subunit βc to promote the expansion and survival of multiple myeloid cells including monocytes/macrophages, neutrophils and eosinophils. Methods: We have used our unique human βc receptor transgenic (hβcTg) mouse strain that expresses human βc instead of mouse βc and βIL3 in an acute CS exposure model. Lung tissue injury was assessed by histology and measurement of albumin and lactate dehydrogenase levels in the bronchoalveolar lavage (BAL) fluid. Transgenic mice were treated with an antibody (CSL311) that inhibits human βc signalling. Results: hβcTg mice responded to acute CS exposure by expanding blood myeloid cell numbers and recruiting monocyte‐derived macrophages (cluster of differentiation 11b+ [CD11b+] interstitial and exudative macrophages [IM and ExM]), neutrophils and eosinophils into the lungs. This inflammatory response was associated with lung tissue injury and oedema. Importantly, CSL311 treatment in CS‐exposed mice markedly reduced myeloid cell numbers in the blood and BAL compartment. Furthermore, CSL311 significantly reduced lung CD11b+ IM and ExM, neutrophils and eosinophils, and this decline was associated with a significant reduction in matrix metalloproteinase‐12 (MMP‐12) and IL‐17A expression, tissue injury and oedema. Conclusion: This study identifies CSL311 as a therapeutic antibody that potently inhibits immunopathology and lung injury caused by acute CS exposure. Myeloid cells, including macrophages, neutrophils and eosinophils, are important cellular drivers of inflammation and injury. In this study, we blocked granulocyte monocyte‐colony stimulating factor, IL‐5 and IL‐3 signalling with an anti‐βc receptor antibody (CSL311), which greatly reduced lung inflammation and injury in a pre‐clinical model of acute cigarette smoke exposure. [ABSTRACT FROM AUTHOR]