Objective To explore the “medicine-efficacy” associations of traditional Chinese medicine (TCM) in the treatment of sepsis, identify core herbsrelated to reducing mortality and improving key clinical outcomes such as the acute physiology and chronic health evaluation II (APACHE II) score, and provide evidence-based references for TCM-assisted treatment of sepsis. Methods A systematic search of Chinese and English databases was conducted up to September 2024 to collect clinical studies on TCM compound prescriptions for sepsis. A comprehensive sepsis TCM formula database was established. Nine machine learning algorithms were compared using ten-fold cross-validation, and the optimal model for each clinical outcome was interpreted through the Shapley additive explanations (SHAP) method to identify key herbs and their contribution directions. Results The multilayer perceptron showed the best performance in predicting TCM syndrome scores, overall effectiveness, inflammatory and immune indicators, biochemical parameters, organ dysfunction scores, and mortality; logistic regression performed best for blood gas analysis along with gastrointestinal function and intestinal mucosal barrier outcomes; and the support vector machine achieved optimal predictive performance for routine blood tests and APACHE II scores. SHAP analysis revealed that Dihuang (Rehmanniae Radix), Zhishi (Aurantii Fructus Immaturus), Huangqi (Astragali Radix), Fuzi (Aconiti Lateralis Radix Praeparata), Huangqin (Scutellariae Radix), and Houpo (Magnoliae Officinalis Cortex) had positive contributions across outcomes such as mortality, APACHE II score, inflammatory markers, and gastrointestinal function, forming the core nodes of the “medicine-efficacy” network. Conclusion This study established a clinically oriented “medicine-efficacy” association network through multi-model comparison and explainable machine learning analysis. The findings highlight the potential key roles of several core herbs in improving major clinical outcomes of sepsis, providing data support and evidence-based basis for precise syndrome differentiation and medication in TCM, as well as for the research and development of new TCMs.

sepsis  /  traditional Chinese medicine formulas  /  machine learning  /  SHAP  /  “medicine-efficacy” rule  /  data mining  /  Rehmanniae Radix  /  Aurantii Fructus Immaturus  /  Astragali Radix  /  Aconiti Lateralis Radix Praeparata  /  Scutellariae Radix  /  Magnoliae Officinalis Cortex