ETHNOPHARMACOLOGICAL RELEVANCE: Banxia Xiexin Decoction (BXD) is a representative prescription to regulate spleen and stomach in "Treatise on Febrile Diseases", which has been proven effective for the clinical treatment of irritable bowel syndrome (IBS) in the past decades. However, the active principles and molecular mechanisms involved in BXD against IBS are vague yet. AIM OF THE STUDY: To unfold multicomponent synergy mechanism of BXD on irritable bowel syndrome, this work explored active principles, drug targets and crucial pathways using a systems pharmacology strategy. MATERIALS AND METHODS: In this study, a systems pharmacology based strategy was applied by the procedures integrating compound database construction, ADME evaluation, target identification, functional annotation, pathway enrichment analysis, network analysis, and molecular docking verification. The 158 compounds from BXD were selected for the screening. The Compound-Target network (C-T) and the Target-Pathway network (T-P) were constructed. The bioinformatics and network topology were employed to systematically reveal multicomponent-target interactions of BXD. The affinity between important ingredients and the kernel targets was validated using molecular mechanics simulation. RESULTS: The 35 potential important ingredients and the 16 associated kernel targets were identified. 27 crucial pathways, in which the kernel targets participated, could regulate the biological processes, such as synthesis of inflammatory mediators, smooth muscle relaxation and synaptic plasticity, closely related to pathological mechanism of IBS. The cross-talk interactions were revealed between TNF signaling pathway, Dopaminergic synapse and cGMP-PKG signaling pathway, which would exert the synergistic influences on the occurrence and treatment of the IBS. PTGS2, CALM, NOS2, SCN5A, and PRSS1 might become novel drug targets for IBS. CONCLUSIONS: The study demonstrated that the synergy molecular mechanisms of BXD mainly involved three therapeutic modules including inhibiting inflammatory reaction, maintaining intestinal function and improving psychological regulation via the multicomponent-target interaction networks. It may also provide the promising drug targets and therapeutic agents for the development of new medicines.