Objective: To explore the mechanism of Shanggan granules on pulmonary inflammation in mice infected with influenza virus. Methods: The model of pulmonary infection with influenza virus was established by nasal inoculation with influenza A/PR8/34 virus. The groups were divided into normal control group, model group, positive control group, low-dose Shanggan granules group, medium-dose Shanggan granules group, and high-dose Shanggan granules group. The treatment lasted for 7 days. After the experiment, the body weight and lung wet weight of the mice were detected. Hematoxylin-eosin staining was used to observe the pathological changes of the lung tissues. The levels of TNF-α, IL-6, IL-8, and TGF-β in the lung tissues were detected by enzyme linked immunosorbent assay. SOD, GSH-Px, and MDA in lung tissues were detected by the kit method. TLR4/NF-κB inflammatory signaling pathways were detected by real-time PCR. Western blot detects the TKB1/IRFs signaling pathway. Results: Compared with the model group, both Shanggan Granules and oseltamivir phosphate reduced the wet weight of the lungs in mice infected with influenza virus, decreased the infiltration of inflammatory cells in lung tissue, reduced the levels of inflammatory factors TNF-α, IL-6, IL-8 and TGF-β, decreased the levels of SOD and GSH-Px in lung tissue, and increased the level of MDA. In addition, mRNA levels of TLR4, MyD88 and p38 and protein expression of TKB1/IRF3/7/NF-κB signaling pathway were inhibited. Conclusion: Shanggan granules could effectively reduce lung injury, lung inflammation, and oxidative stress, and its mechanism might be related to the down-regulation of TLR4/NF-κB inflammatory signaling pathways.