Objective To explore the mechanism of Shanggan granules in suppressing pulmonary inflammation in mice infected with H1N1 influenza virus. Methods A mouse model of pulmonary influenza virus infection was established by nasal inoculation with H1N1 influenza virus. Mice were divided into a normal control group, model group, positive control group, and low-, medium-, and high-dose Shanggan granules groups. Mice were treated for 7 days and then sacrificed, and the body weight and lung wet weight were measured. Pathological changes in the lung tissues were detected by hematoxylin/eosin (HE) staining. Tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and transforming growth factor-β (TGF-β) levels in lung tissues were detected by enzyme-linked immunosorbent assay, and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) were detected using appropriate kits. Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) inflammatory signaling pathways were detected by real-time polymerase chain reaction, and TANK-binding kinase 1 (TBK1)/ interferon regulatory factor (IRF) signaling pathway proteins were detected by Western blot. Results Both Shanggan granules and oseltamivir phosphate reduced the lung wet weight (P<0.05, P<0.001) in mice infected with influenza virus H1N1 compared with the model group, decreased the infiltration of inflammatory cells in lung tissue, reduced levels of the inflammatory factors TNF-α, IL-6, IL-8, and TGF-β (P<0.05, P<0.01, P<0.001), decreased levels of SOD and GSH-Px in lung tissue (P<0.05, P<0.01), and increased MDA levels (P<0.05, P<0.01). Shanggan granules and oseltamivir phosphate also reduced TLR4, MyD88, and p38 mRNA levels (P<0.05, P<0.01) and expression of TBK1/IRF3/7/NF-κB signaling pathway proteins (P<0.05, P<0.01, P<0.001). Conclusions Shanggan granules may effectively reduce lung injury, lung inflammation, and oxidative stress, via a mechanism related to the down-regulation of TLR4/NF-κB inflammatory signaling pathways.