Non‐technical summary  Mucin secretion in the lung is regulated by the soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE) exocytotic core, which has not been defined in airway goblet cells. In this study, the SNARE vesicle‐associated membrane protein 8 (VAMP8) was found to be expressed in human airway epithelial goblet cells. VAMP8 knockdown by RNA interference techniques reduced airway epithelial mucin secretion induced by PAR agonists, neutrophil elastase and ATP. Basal (non‐agonist elicited) mucin secretion was also reduced as a result of VAMP8 knockdown. Importantly, mucin secretion was reduced in the lungs of VAMP8 knockout mice compared to wild‐type littermates. Our data suggest that VAMP8 is an essential SNARE in airway mucin granule exocytosis. Reduction of VAMP8 activity/expression may provide a novel therapeutic target to ameliorate airway mucus obstruction in lung diseases.