As a medicinal plant, Cirsium setosum has excellent procoagulant effects and has long been used as a cure for hemoptysis, epistaxis, uremia and metrorrhagia caused by blood heat. However, the key medicinal part of C. setosum, as well as the biologically active substances that play a major role, are not known. In this study, the aboveground, underground and whole grass portions of C. setosum were subjected to a coagulation comparison experiment to determine the primary active procoagulant compounds. The main active procoagulant compounds of C. setosum were then screened using a comparative metabolomics analysis between aboveground and underground. Network pharmacology analysis was used to construct the “active ingredient-disease target-pathway” network. Finally, molecular docking was used to verify the binding ability and affinity between the key active ingredients obtained from the screening and the targets. The results indicated that the aboveground part of C. setosum could significantly shorten activated partial thromboplastin time (APTT) and that this part exerts substantial procoagulant effects. The total phenol, total flavonoid and total alkaloid content of the aboveground part was measured to be higher than those of the underground part and whole grass. Furthermore, comparative metabolomics analysis as well as the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database and literature search screening yielded 10 active substances, including naringenin, guanine, 2,4-di-tert-butylphenol, calycosin-7-O-beta-D-glucoside, flavone, vitexin, and tiliroside, which may be related to the coagulation-promoting properties of C. setosum and its therapeutic effects on coagulation-related disorders. Network pharmacological analysis revealed that C. setosum may exert procoagulant effects mainly through tiliroside, calycosin-7-O-beta-D-glucoside, and flavone, which act on key target proteins, such as SRC, PRKACA, EGFR, AKT1, MAPK3, and GSK3B. In summary, C. setosum exerts its procoagulant and therapeutic effects on coagulation-related diseases through multiple compounds, targets, and pathways.