Objective To investigate the mechanism by which Xuanfei Jiedu Formula (XFJDF) ameliorates pulmonary damage in rats with multidrug-resistant Pseudomonas aeruginosa (MDR-PA) pneumonia, by modulating the activity of the inhibitor of nuclear factor (NF)-κB kinase (IKK) IKK/NF-κB signal transduction cascade. Methods Eighty-four rats were divided randomly into seven groups: control, model, XFJDF-low dose, XFJDF-medium dose, XFJDF high dose, imipenem (IPM), and pyrrolidinedithiocarbamate ammonium (PDTC) groups (n=12 rats per group). A MDR-PA pneumonia rat model was established by oral tracheal intubation. After successful model construction, rats in the low-, medium-, and high-dose XFJDF groups were given the corresponding dose of drugs by gavage, rats in the IPM group were given an intraperitoneal injection of IPM, and rats in the control and model groups were given the same volume of normal saline by gavage, twice a day for 7 days. PDTC was injected intraperitoneally 1 h before model establishment, 12 h and 24 h after model establishment in the NF-κB inhibitor group. The behavior status, body weight changes, spleen and thymus indexes, and lung wet weight/dry weight ratio were observed in the different groups. Histological changes in the lung tissue were assessed by hematoxylin and eosin staining. Terminal deoxynucleotidyl transferase dUTP nick end labeling was used to detect apoptosis of lung tissue cells, and serum levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and IL-10 were detected by enzyme-linked immunosorbent assay, and glutathione (GSH) and malondialdehyde (MDA) levels, myeloperoxidase (MPO) activity and total antioxidant capacity (T-AOC) were determined by colorimetry and thiobarbituric acid assay. NF-κBp65 in lung tissue was identified by immunohistochemical analysis, IKKβ and NF-κBp65 mRNA were analyzed by reverse transcription quantitative polymerase chain reaction, and expression levels of IKKβ, phosphorylated (p)-IKKβ, NF-κBp65, and p-NF-κBp65 were measured by Western blot. Results Compared with the control group, rats in the model group exhibited decreased appetite, dull fur, sluggish responsiveness, decreased mobility, increased respiratory rate, audible murmurs, and notable weight loss (P<0.01). The spleen and thymus indices were significantly enhanced (P<0.01) and the lung wet/dry weight ratio was significantly increased (P<0.01), concurrent with increased alveolar secretions in lung tissue. Infiltration of abundant inflammatory cells and increased apoptosis in lung tissue were also noted. Serum concentrations of IL-1β, TNF-α, TGF-β, and IL-10 were increased (P<0.01) and the MDA content and MPO activity were also increased (P<0.01). Conversely, GSH levels and T-AOC were significantly decreased (P<0.01). Lung levels of IKKβ and NF-κBp65 mRNA were significantly increased (P<0.01) and the ratios of p-IKKβ/IKKβ and p-NF-κBp65/NF-κBp65 were also significantly increased (P<0.01) compared with the control group. XFJDF, IPM and PDTC improved these parameters to varying degrees, compared with the model group (P<0.05, P<0.01), with particularly significant effects in the high-dose XFJDF and IPM groups. Conclusions XFJDF may improve lung injury in rats with MDR-PA pneumonia by inhibiting the IKK/ NF-κB signaling pathway.