Objective To explore the effect of down-regulation of high mobility group box 1 (HMGB1) expression on inflammatory response and epithelial mesenchymal transition (EMT) in the lung tissue of mice with chronic obstructive pulmonary disease (COPD) and its related mechanism. Methods The COPD model was induced by cigarette smoking, and HMGB1 expression in lung tissue of mice was down-regulated by small interfering RNA (siRNA). The mice were divided into negative control group (NC group), COPD group, si-NC intervention COPD group, si-HMGB1 intervention COPD group, and tiotropium bromide intervention COPD group (positive control group). After 4 weeks of cigarette smoking induction, the general condition of mice were observed, and the body mass changes of each group were recorded every week. HE staining was used to observe the pathological changes of lung tissue in each group. The expression of HMGB1 mRNA and protein in lung tissues of mice weredetected by real time quantitative PCR and Western blot analysis. The BALF of mice in each group was collected, and the levels of IL-6, TNF-α, IL-1β and TGF-β1 in BALF were detected by ELISA. The expressions of E-cadherin and α-SMA in lung tissues of mice were observed by immunohistochemical staining. The expression of RAGE, TLR4, TGF-β1 and the phosphorylation of NF-κB p65 in lung tissues were detected by Western blot analysis. Results COPD mouse model induced by cigarette smoking was successfully established. Compared with COPD group, down-regulation of HMGB1 expression in lung tissue significantly improved the general vital signs of mice, promoted the increase of body mass, and improved the pathological damage of lung tissue in mice. Compared with the control group, HMGB1 mRNA and protein expression levels increased significantly in COPD group, COPD combined with si-NC group and COPD combined with tiotropium group, while no significant HMGB1 expression was detected in COPD combined with si-HMGB1 group. Compared with the control group, the secretion levels of IL-6, TNF-α, IL-1β, TGF-β1 in BALF, the expression levels of α-SMA, RAGE, TLR4, TGF-β1 and the phosphorylation level of NF-κB p65 in lung tissues were significantly increased in COPD model group, while the expression level of E-cadherin significantly decreased. Compared with the COPD group or the COPD combined with si-NC group, the changes of the above indexes in the lung tissue of mice in the COPD combined with si-HMGB1 group and the COPD combined with tiotropium group dropped markedly, and no significant difference between the latter two groups was found. Conclusion Downregulation of HMGB1 expression in lung tissue of mice can reduce pulmonary inflammatory response and EMT by inhibiting NF-κB pathway, thus ameliorating the progression of cigarette smoke-induced COPD disease.