Objective To investigate the effect of sivelestat sodium on the glucose-regulated protein 78 / protein kinase R-like endoplasmic reticulum kinase / CCAAT enhancer-binding protein homologous protein (GRP78 / PERK/ CHOP) signaling pathway and airway hypersecretion in rats with chronic obstructive pulmonary disease (COPD). Methods The COPD rat model was established by exposure to cigarette smoke combined with endotracheal instillation of lipopolysaccharide (LPS). The model rats were randomly divided into a COPD group, sivelestat sodium intervention groups (low, medium, and high dose), and a control group (NC group) of normal rats, with 12 rats in each group. The rats in the low, medium, and high dose sivelestat sodium groups were injected via their tail vein with 2. 5 mg / kg, 5. 0 mg / kg, and 10. 0 mg / kg sivelestat sodium, respectively, and the NC group and COPD group were injected with the same amount of normal saline twice a day for 21 days. The levels of lung function indexes, including the forced expiratory volume in 0. 1 s (FEV0. 1) and forced vital capacity ( FVC), were measured. The apoptosis of alveolar epithelial cells was detected by TdT-mediated dUTP nick and labeling (TUNEL), and microscope histopathological changes of the rat lungs were assessed. The mRNA expression levels of mucin 5AC(MUC5AC), glucose-regulated protein 78(GRP78), protein kinase R-like endoplasmic reticulum kinase(PERK), and CCAAT/ enhancer binding protein homologous protein(CHOP) were detected by real-time fluorescence quantitative PCR (RT-qPCR), and the protein expression of MUC5AC, GRP78, PERK, and CHOP in the lung tissue of rats was detected by Western blot. Results In the NC group, the alveolar structure was intact without obvious pathological changes. In the COPD group rats, the wall thickness of lung tissues was increased, the wall of alveoli was thin, the cilia were collapsed and detached, and there was extensive inflammatory cell infiltration. However, the pathological changes in the lung tissue of rats in each sivelestat sodium intervention group were alleviated. Compared with those in the NC group, the FEV0. 1 and FVC in the COPD group were significantly lower, the apoptosis rate of alveolar epithelial cells was higher, and the mRNA and protein levels of MUC5AC, GRP78, PERK, and CHOP in lung tissues were significantly increased (P< 0. 05). Compared with those in the COPD group, the FEV0. 1 and FVC in the rats in the low, medium, and high dose sivelestat sodium groups were increased, the apoptosis rate of alveolar epithelial cells was reduced, and the mRNA and protein levels of MUC5AC, GRP78, PERK, and CHOP in lung tissues were decreased (P< 0. 05). Conclusions Sivelestat sodium can reduce airway mucus hypersecretion in COPD rats, which may be related to the inhibition of GRP78 / PERK/ CHOP signaling pathway activation and reduction in lung epithelial cell apoptosis in COPD.