Background <p>Intrauterine adhesion (IUA), which impairs endometrial function, lacks effective treatments. Guizhi Fuling Pills (GFPs), a traditional Chinese medicine historically used for gynecological conditions, represent a promising therapeutic candidate.</p> Aim <p>The present study examined the effects of GFPs and its possible mechanisms against IUA by reducing inflammatory responses.</p> Methods <p>Network pharmacology and experimental validation were conducted to identify possible targets of GFPs. 100 IUA patients and 100 control patients with benign gynecological diseases were enrolled. The expression of TNF/AKT1/NFKBIA was measured in endometrial tissues of all subjects using RT-qPCR. The levels of inflammatory factors in the patients’ serum before the operation were also measured by ELISA. The anti-inflammatory effects of GFPs were evaluated based on an inflammation cell model.</p> Results <p>According to network pharmacology, TNF/AKT1/NFKBIA was identified as one central acting pathway of GFPs. Compared with the controls, the levels of inflammatory factors (TNF-α, IL-6, IL-1β) in the serum of IUA patients were higher. Clinical samples indicated that TNF and AKT1 were both expressed at an up-regulated level in the endometrium of IUA patients, while NFKBIA was down-regulated. These expression levels were significantly associated with American Fertility Society (AFS) score. Experiments confirmed that GFPs-containing serum could reverse the LPS-induced inflammatory phenotype of hEECs, inhibit the expression of TNF/AKT1, upregulate NFKBIA, and suppress phosphorylation of AKT/IκBα/p65. GFPs inhibited LPS-induced cell damage, suppressed cell apoptosis, reduced the secretion of TNF-α, IL-6, and IL-1β, and attenuated epithelial-mesenchymal transition (restoring E-cadherin, reducing N-cadherin and α-SMA).</p> Conclusions <p>GFPs may ameliorate IUA via the TNF/AKT1/NFKBIA axis, offering a promising therapeutic approach for IUA treatment based on traditional Chinese medicine.</p>