Cigarette smoke (CS) is considered a principal cause of chronic obstructive pulmonarydisease (COPD) and is associated with mucus hypersecretion and airway inflammation. Ginsenosidecompound K (CK), a product of ginsenoside metabolism, has various biological activities. Studies on theeffects of CK for the treatment of COPD and mucus hypersecretion, including the underlying signalingmechanism, have not yet been conducted. Methods: To study the protective effects and molecular mechanism of CK, phorbol 12-myristate 13-acetate (PMA)-induced human airway epithelial (NCIeH292) cells were used as a cellular model ofairway inflammation. An experimental mouse COPD model was also established via CS inhalation andintranasal administration of lipopolysaccharide. Mucin 5AC (MUC5AC), monocyte chemoattractantprotein-1, tumor necrosis factor-a (TNF-a), and interleukin-6 secretion, as well as elastase activity andreactive oxygen species production, were determined through enzyme-linked immunosorbent assay. Inflammatory cell influx and mucus secretion in mouse lung tissues were estimated using hematoxylinand eosin and periodic acideschiff staining, respectively. PKCd and its downstream signaling moleculeswere analyzed via western blotting. Results: CK prevented the secretion of MUC5AC and TNF-a in PMA-stimulated NCIeH292 cells andexhibited a protective effect in COPD mice via the suppression of inflammatory mediators and mucussecretion. These effects were accompanied by an inactivation of PKCd and related signaling in vitro andin vivo. Conclusion: CK suppressed pulmonary inflammation and mucus secretion in COPD mouse modelthrough PKC regulation, highlighting the compound's potential as a useful adjuvant in the preventionand treatment of COPD.