The proper regulation of Zinc (Zn) trafficking proteins and the cellular distribution of Zn is critical for the maintenance of autophagic processes. However, there have been no studies which have examined Zn dyshomeostasis and the disease-related modulation of autophagy observed in the airways afflicted with COPD. We hypothesized that dysregulated autophagy in airway epithelial cells (AEC) is related to Zn dysregulation in cigarette smoke (CS)-induced COPD. We applied a human ex vivo air-liquid interface model, a murine model of smoke-exposure, and human lung tissues, and investigated Zn, ZIP1 and ZIP2 Zn-influx proteins, autophagy (Microtubule-associated 1A/1B-light chain-3 (LC3), Beclin-1), autophagic flux (Sequestosome), apoptosis (Bcl2; X-Linked Inhibitor of Apoptosis (XIAP), Poly (ADP)-ribose Polymerase (PARP)), and inflammation (TSLP, RANTES, and IL-1β). Lung tissues from CS-exposed mice exhibit reduced free-Zn in AEC, with elevated ZIP1 and diminished ZIP2 expression. Interestingly, increased LC3 co-localized with ZIP1, suggesting an autophagic requirement for free-Zn to support its catabolic function. In human AECs, autophagy was initiated, but was unable to efficiently degrade cellular debris, as evidenced by stable Beclin-1 and increased LC3-II, but with a concomitant elevation in Sequestosome. Autophagic dysfunction due to CS-exposure coupled with Zn depletion also induced apoptosis, with the reduction of anti-apoptotic and anti-autophagic proteins Bcl2 and XIAP, and PARP cleavage. This was accompanied by an increase in RANTES, and TSLP, an activator of adaptive immunity. We conclude that the uncoupling of Zn-trafficking and autophagy in AEC may be a fundamental disease-related mechanism for COPD pathogenesis, and provide a new therapeutic target.