Diarrhea continues to be a major public health problem and is thought to be the cause of 525,000 child fatalities annually. Studies have shown that Macleaya cordata (Willd.) R.Br., Papaveraceae, has a good therapeutic effect on diarrhea due to its action on ion channels. However, its antidiarrheal mechanisms and key targets are not supported by scientific research. This study aimed to identify the mechanisms of action and targets of the primary active antidiarrheal compounds of M. cordata . We used network pharmacology and molecular docking to identify the antidiarrheal mechanisms and the key targets of M. cordata and its main chemical constituents. Subsequently, the experiments performed with dihydrosanguinarine (25, 50, and 100 mg/kg), which included the evaluation of the inhibitory potential of the epidermal growth factor receptor in osimertinib-induced diarrhea, real-time quantitative PCR, and western blotting, were performed for further verification of its mechanism of action. The findings revealed that of all the genes, tyrosine-protein kinase Lck, receptor tyrosine-protein kinase Erbb2, and epidermal growth factor receptor had the highest capacity of action, and the NF-kappa B and the calcium signaling pathways may play essential roles in M. cordata against diarrhea. Dihydrosanguinarine is the most active ingredient, and it significantly inhibits the increase in incidence and decreased the fecal water content of osimertinib-induced diarrhea. Western blot and qRT-PCR showed that dihydrosanguinarine works as an antidiarrheal agent by upregulating the expression of the core target epidermal growth factor receptor, affecting the NF-kappa B and the calcium ion signaling pathways, downregulating the expression of calcium-activated chloride channel and NK-kappa B P-65. Graphical Abstract