Background <p>Sepsis-associated acute gastrointestinal injury (SAGI) represents a core pathological mechanism contributing to high mortality rates in critically ill patients, fundamentally rooted in a vicious cycle between uncontrolled systemic inflammatory responses and intestinal barrier dysfunction. Aucklandiae Radix (Muxiang), a traditional Chinese medicinal herb, exhibits multiple pharmacological activities including anti-inflammatory, antioxidant, and gastrointestinal mucosal barrier protective effects, suggesting significant potential for intervening in SAGI. However, the specific therapeutic efficacy of Aucklandiae Radix against SAGI and its underlying molecular mechanisms remain to be systematically elucidated.</p> Methods <p>A sepsis-associated acute gastrointestinal injury (SAGI) model was established using cecal ligation and puncture (CLP). By evaluating survival rates, intestinal microstructural alterations, serum inflammatory cytokine levels, and intestinal tissue oxidative stress markers across different mouse groups, preliminary evidence was obtained demonstrating the potential therapeutic effect of Aucklandiae Radix on SAGI. Subsequently, active components of Aucklandiae Radix were screened using the TCMSP database. Potential targets for Aucklandiae Radix intervention in SAGI were identified by integrating data from GEO, PubChem, SwissTargetPrediction, and GeneCards databases. The STRING database was used to construct a protein interaction network and screen core targets. Gene functional enrichment analysis was performed using the DAVID database. Finally, the CB-Dock2 molecular docking platform was employed to validate the binding affinity between active components and core targets and visualize the results.</p> Results <p>Animal experiments revealed that after treatment with Aucklandiae Radix, model mice exhibited increased daily food and water intake, while the 7-day survival rate rose from 13.5 to 33.3% and 53.3% (<i>P</i> &lt; 0.05). Histopathological examination further demonstrated that Aucklandiae Radix reduced inflammatory cell infiltration in the submucosal layer of the intestine and alleviated villous edema, while promoting structural repair of the intestinal barrier. At the molecular level, treatment with Aucklandiae Radix significantly reduced levels of oxidative stress markers (MDA, SOD, and GSH-Px) in intestinal tissues and pro-inflammatory cytokines (IL-1β and TNF-α) in serum. Collectively, these findings suggest that Aucklandiae Radix may exert protective effects against sepsis-induced acute gastrointestinal injury by enhancing intestinal antioxidant defenses and suppressing systemic inflammatory responses. Based on network pharmacology and bioinformatics analysis, three key active components of Aucklandiae Radix and six core targets for their intervention in SAGI were identified. Gene enrichment analysis revealed significant activation of the IL-17 signaling pathway. Molecular docking results demonstrated high affinity between the active components and core targets.</p> Conclusion <p>This study employed a logical chain from phenotype to target, preliminarily validating the therapeutic effect of Aucklandiae Radix on SAGI through animal experiments. Network pharmacology methods were then applied to identify the potential molecular mechanisms underlying Aucklandiae Radix’s treatment of SAGI. Network pharmacology and molecular docking results suggest that IL-17, as a potential signaling pathway, may play a crucial role in the treatment of SAGI by Aucklandiae Radix. This provides potential targets and significant reference value for future development of new clinical drugs and basic research.</p> Graphical Abstract <p></p>