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COPD is the third leading cause of death worldwide, but current therapies for COPD are only effective at treating the symptoms of the disease rather than targeting the underlying pathways that are driving the pathogenic changes. The lack of targeted therapies for COPD is in part due to a lack of knowledge about drivers of disease progression and the difficulty in building relevant and high throughput models that can recapitulate the phenotypic and transcriptomic changes associated with pathogenesis of COPD. To identify these drivers, we have developed a cigarette smoke extract (CSE)-treated bronchosphere assay in 384-well plate format that exhibits CSE-induced decreases in size and increase in luminal secretion of MUC5AC. Transcriptomic changes in CSE-treated bronchospheres resemble changes that occur in human smokers both with and without COPD compared to healthy groups, indicating that this model can capture human smoking signature. To identify new targets, we ran a small molecule compound deck screening with diversity in target mechanisms of action and identified hit compounds that attenuated CSE induced changes, either decreasing spheroid size or increasing secreted mucus. This work provides insight into the utility of this bronchosphere model in examining human respiratory diseases, the pathways implicated by CSE, and compounds with known mechanisms of action for therapeutic development.