Abstract：Objective：To observe the effect and regulatory mechanism of Qingre Sanjie Tablets on inflammation in rats with secretory otitis media. Methods：A total of 60 healthy male SD rats were divided into six groups（n=10 per group）using the random number table method： the control group， the model group， the low-/medium-/high-dose Qingre Sanjie Tablets intervention groups（0.135，0.27，0.54 g/kg，respectively），and the prednisone group（prednisone 5 mg/kg）. Except for the control group，animal models with secretory otitis media were established in the other groups using an endotoxin induction method. After successful modeling，the control and model groups received equal volumes of 0.9% sodium chloride solution，while the drug intervention groups were administered the corresponding doses via oral gavage daily for 21 consecutive days. Pathological morphological characteristics of the middle ear mucosa were examined using Hematoxylin-Eosin（HE）staining, and typical pathological indicators such as inflammatory infiltration，epithelial integrity，and glandular hyperplasia in the tympanic mucosa of rats from each group were systematically evaluated under light microscopy. Serum levels of tumor necrosis factor-α（TNF-α），interleukin（IL）-1β，IL-8，IL-6，IL-2，IL-4， and interferon-γ（IFN-γ）were measured by enzyme-linked immunosorbent assay（ELISA）. The mRNA and protein expression levels of TLR4，MyD88，and NF-κB in the tympanic mucosa were detected by real-time quantitative PCR （RT-qPCR）and Western blot，respectively. Results：Compared with the control group，the model group exhibited significant pathological damage in the tympanic mucosa，elevated serum levels of TNF-α，IL-6，IL-1β，and IL-4， decreased levels of IFN-γ and IL-2（P＜0.05），and upregulated mRNA and protein expression of TLR4/MyD88/NF-κB pathway components（P＜0.05）. Compared with the model group， all Qingre Sanjie Tablets dose groups and the prednisone group showed alleviated pathological damage，reduced serum levels of TNF-α，IL-6，IL-1β，and IL-4， increased levels of IFN-γ and IL-2（P＜0.05）， and downregulated mRNA and protein expression levels of TLR4/ MyD88 / NF - κB pathway in middle ear mucosa tissue（P＜0.05）. Conclusion： Qingre Sanjie Tablets ameliorate inflammatory responses in rats with secretory otitis media by suppressing the TLR4/MyD88/NF-κB signaling pathway.