Cigarette-smoke (CS) exposure and aging are the leading causes of chronic obstructive pulmonary disease development, however, the mechanism for the occurrence and treatment of emphysema is still not fully understood. In a previous study, we identified microRNA (miRNA) mRNA correlations that are related to impaired autophagy and cellular senescence in CSE-exposed epithelial cell new-generation sequencing. The air-liquid interface (ALI) exposure method was the most similar to human inhalation exposure. Therefore, we confirmed the role of miR-149-3p in impaired autophagy and cellular senescence by CSE exposure on the ALI culture model using normal human bronchial epithelial (NHBE) cells. MiR-149-3p was downregulated in CSE-induced NHBE ALI cells and induced impaired autophagy by increased expression levels of p62 and cellular senescence by an increased number of senescent cells presented. CSE exposure markedly increased the expression levels of mRNA as part of the senescence-associated secretory phenotype (SASP) factors (IL-1b, IL-6, IL-8, MCP-1, TNF-a). From these results, we confirmed that the overexpression of miR-149-3p mimic decreased the expression level of p62 and the expression levels and production of SASP factors. In addition, we confirmed the association between miR-149-3p and NDRG1 using TargetScan and found that mRNA and protein levels of NDRG1 were negatively regulated by miR-149-3p. Therefore, we suggest that miR-149-3p regulates CSE-induced impaired autophagy and senescence through targeting NDRG1 in NHBE ALI cells, which provides important evidence for potential therapeutics