Abstract： Objective： To observe the clinical efficacy of the Tongfu Qingyi Xiere Decoction in treating severe acute pancreatitis （SAP） and its effect on the p38 mitogen-activated protein kinase （p38MAPK）/nuclear factor-kappa B （NF-κB） signaling pathway. Methods：A total of 96 SAP patients admitted to the Dingqiao Campus， Hangzhou Traditional Chinese Medicine Hospital of Zhejiang Chinese Medical University from May 2023 to May 2025 were randomly divided into an observation group and a control group using the random number table method，with 48 cases each. The control group received conventional western medical therapy， while the observation group was treated with Tongfu Qingyi Xiere Decoction in addition to the control group's regimen. Both groups underwent a treatment course of two weeks. The clinical efficacy，incidence of adverse reactions，as well as pre- and post-treatment traditional Chinese medicine syndrome scores，disease severity [Acute Physiology and Chronic Health EvaluationⅡ（APACHE-Ⅱ） score]， p38MAPK and NF-κB protein expression levels， and levels of serum inflammatory factors [interleukin-6 （IL-6）， interleukin-8 （IL-8）， tumor necrosis factor-α （TNF-α）] were compared between the two groups. Results： After treatment， the total effective rate in the observation group was 95.83% （46/48）， while that in the control group was 81.25% （39/48），the difference being significant （P＜0.05）. After treatment，both groups showed reduced scores for traditional Chinese medicine syndrome and APACHE-Ⅱcompared to before treatment （P＜0.05），with the observation group scoring lower in both categories than the control group （P＜0.05）. After treatment， the expression levels of p38MAPK and NF-κB proteins were lower than those before treatment in both groups （P＜0.05），with the observation group exhibiting lower levels for both indicators than the control group （P＜0.05）. After treatment， serum levels of IL-6， IL-8， and TNF-α decreased compared to before treatment in both groups （P＜0.05）， with the observation group showing lower levels for all three indicators than the control group （P＜0.05）. During the treatment period，the incidence of adverse reactions was 6.25% （3/48） in the observation group and 8.33% （4/48） in the control group，with no significant difference between the two groups （P＞0.05）. Conclusion：Tongfu Qingyi Xiere Decoction demonstrates significant therapeutic effects in the treatment of SAP，effectively reducing traditional Chinese medicine syndromes and alleviating disease severity of patients. The mechanism may be related to the inhibition of the p38MAPK/NF- κB signaling pathway and attenuation of systemic inflammatory responses.