Objective Study on mechanism of Xuanfei Jiedu Formula in treating multi-drug resistant Pseudomonas aeruginosa pneumonia. Methods Except the Control group, the MDR-PA (9 × 10⁸ CFU/ mL, 0. 5 mL) pneumonia rat model was established by tracheal intubation, and an un-modeled control group was used. After successful modeling, rats were randomly divided into model group, XFJDF-low dose group, XFJDF-medium dose group, XFJDF-high dose group and IPM group, with 12 animals in each group; In addition to the blank group and the model group, the remaining drug administration groups were collectively referred to as the intervention treatment group. One day after modeling, the XFJDFlow dose, XFJDF-medium dose, and XFJDF-high dose groups were given the corresponding doses by gavage. The imipenem and cilastatin group was given Imipenem intraperitoneal injection, and the control and model groups were given saline gavage twice a day for 7 days. The rats’ general status, body weight changes, and wet-dry weight ratio (W/ D) of the lung tissue were observed. Hematoxylin-eosin staining was used to observe the pathological changes to the lung tissue of rats in each group under a light microscope. The serum levels of IL-1β, TGF-β, TNF-α, and IL-6 were detected by enzyme immunosorbent assay. Serum GSH content and MPO activity of rats were detected by colorimetry. The serum content of MDA was detected by TBA method. The total antioxidant capacity (T-AOC) was detected by kit method. The protein levels of TLR4, Myd88, and NF-κBp65 in lung tissues were determined by immunohistochemistry. The mRNA and protein levels of TLR4, Myd88, and NF-κBp65 in the lung tissues of each group were detected by qPCR and Western Blot. Results Compared with the control group, the model groups had delayed responses, increased respiratory frequency,increased respiratory noise, and appeared to have different degrees of chills, as well as decreased diet and water intake and decreased body weight. The W/ D of lung tissue was significantly increased ( P<0. 01 ), and a large number of inflammatory cells had infiltrated the alveolar cavity and around the lung bronchus. Some alveolar walls were fractured and fused to form air cavities, with inflammatory exudation, pulmonary interstitial thickening, and local lung fiber formation.The serum levels of IL-1β, TNF-α, TGF-β, and IL-6 were significantly increased ( P<0. 01), MDA content was increased, MPO activity was enhanced, GSH content and T-AOC capacity were decreased (P<0. 01), and the mRNA and protein levels of TLR4, Myd88, and NF-κBp65 in lung tissue were significantly increased (P<0. 01). Compared with the model groups, the intervention group and the treatment group showed improvements in the above indexes (P<0. 05, P<0. 01), and the Xuanfei Jiedu Formula high-dose group and IPM group had the most significant improvements (P<0. 05, P<0. 01). Conclusions Xuanfei Jiedu can significantly improve the general state, body weight, lung tissue W/ D, and lung tissue pathology, and the reduce inflammation and oxidative stress, of MDR-PA rats. The mechanism may be related to its inhibition of the expression of TLR4 / Myd88 / NF-κB pathway proteins in lung tissue.