Objective Cigarette smoke (CS) exposure combined with Klebsiella pneumoniae (KP) infection in mice was used to establish a model of chronic obstructive pulmonary disease (COPD) to investigate the mechanism of airway remodeling. Methods Male BALB/c mice were randomly divided into a Control group, CS group, KP group, and CS + KP group. The mice were exposed to CS, KP, and CS + KP from weeks 1 to 8, and were sacrificed in weeks 4, 8, 16, and 24. MV, Penh, MLI, MAN, and changes in lung pathological structure were detected. The expression levels of IL-1β and TNF-α in lung tissue were detected by ELISA. Collagen deposition was observed by Masson staining and immunohistochemistry. α-SMA and TGF-β1 expression in lung tissue was detected by immunofluorescence. Human bronchial epithelioid cells (16HBE) were also stimulated by CS and lipopolysaccharide (LPS) in vitro, and the expression levels of airway epithelial junction proteins, autophagy-related protein, and mTOR signaling proteins were detected. Results Compared with the Control group, the CS + KP group mice had significantly decreased MV from weeks 4 to 24 (P<0.05 or P<0.01) and significantly increased Penh from weeks 8 to 24 (P<0.05 or P<0.01); while the CS group had markedly decreased MV and markedly increased Penh from weeks 8 to 16 (P<0.05 or P<0.01). Compared with the Control group, massive inflammatory cell infiltration, alveolar wall thickening, alveolar rupture and fusion, and airway wall thickening were observed by HE staining in CS + KP group from weeks 4 to 24. The CS + KP group mice had significantly decreased MAN and significantly increased MLI, IL-1β and TNF-α in their lung tissue from weeks 4 to 24 (P<0.05 or P<0.01). The aforementioned inflammation and tissue damage were observed in the CS group and the KP group from week 8 to 16. Compared with the Control group, COL Ⅰ, COL Ⅲ, α-SMA, and TGF-β1 were significantly increased in lung tissue of mice in the CS + KP group from weeks 8 to 16 (P<0.01); COL Ⅰ was significantly increased in the CS group and KP group from weeks 8 to 16 (P<0.01). In addition, increased E-cad and decreased N-cad (P<0.05); significantly decreased LC3B and Beclin-1 (P<0.05); and significantly increased p-mTORC1, p-P70-S6K, and p-4E-BP1 expression were observed in 16HBE cells exposed to CS and LPS (P<0.05 or P<0.01). Conclusions Pulmonary functional decline, pathological changes in lung tissue, and airway remodeling appeared to occur early and persist in COPD mice induced by CS and KP. The mechanisms may be related to the activation of mTORC1 signaling pathway and subsequent inhibition of autophagy.