Objective To investigate the effect and mechanism of pomalidomide (POM) on airway inflammation and mucus hypersecretion in rats with chronic obstructive pulmonary disease (COPD). Methods Thirty-six SD rats were randomly divided into control group, model group and POM group, with 12 in each group, half male and half female. The COPD model was established by smoke exposure combined with Klebsiella pneumoniae infection in model group and POM group. The rats in POM group were treated with POM (0.5 mg/kg, once a day for 1 week). The lung function, lung tissue pathology, the proportion of inflammatory cells in bronchoalveolar lavage fluid (BALF) and the levels of serum inflammatory factors tumor necrosis factor-α (TNF‑α), interleukin (IL)‑1β, IL-6 and IL‑13 were observed and detected in each group. AB-PAS staining and immunohistochemistry were used to analyze the proliferation of goblet cells and the secretion of mucin (MUC) 5AC and MUC5B in airway epithelium of rats. The expression levels of TNF‑α receptor 1 (TNFR1), IκB kinase (IKK), phosphorylated IKK (p-IKK) and P65 protein in lung tissue were detected by Western blotting. Results Compared with control group, model group showed significant decreased of tidal volume (TV), minute ventilation (MV), forced expiratory vital capacity (FVC), 0.1s forced expiratory volume (FEV0.1) and 0.3 s forced expiratory volume (FEV0.3) (P<0.05), increased of the mean linear intercept (MLI) of the alveoli (P<0.01), decreased of the mean alveolar number (MAN) (P<0.01), increased of the proportion of neutrophils and lymphocytes in BALF sediment (P<0.05), and decreased of the proportion of macrophages in BALF sediment (P<0.01);increased of the levels of serum inflammatory factors TNF-α, IL-1β, IL-13 and IL-6 (P<0.05), the proportion of goblet cells in airway epithelium (P<0.01), the secretion of MUC5AC and MUC5B in lung tissue (P<0.01), the content of TNFR1 and the ratio of p-IKK / IKK (P<0.01), the content of P65 in nucleus (P<0.01); and decreased of the content of P65 in cytoplasm (P<0.05). Compared with model group, after one week of POM treatment, POM group showed significant improved of the TV, MV, FVC, FEV0.1, FEV0.3, MLI and MAN of rats (P<0.05); decreased of the proportion of neutrophils and lymphocytes in BALF (P<0.05); increased of the proportion of macrophages (P<0.01); decreased of the levels of serum TNF-α, IL-1β, IL-6 and IL-13 (P<0.05), the proportion of goblet cells in airway (P<0.01), the secretion of MUC5AC and MUC5B (P<0.01), and the expression of TNFR1, P-IKK and P65 (nucleus) (P<0.05); and increased of the level of P65 (cytoplasm) (P<0.01). Conclusions POM can improve airway inflammation and mucus hypersecretion in COPD rats, which may be achieved by inhibiting TNF-α/NF-κB signaling pathway.