In the present study, the mechanism of Panax notoginseng saponins (PNS), the extract of Panax notoginseng, against deep vein thrombosis (DVT) was explored by networks pharmacology and its effect was demonstrated through clinical data. PNS includes 5 main active components, which have 101 targets. A total of 1,342 DVT-related targets were obtained, 55 of which were the common targets of PNS and DVT. AKT1, TNF, IL1B, EGFR, VEGFA and MAPK3 were selected as hub genes from the protein-protein interaction network. The potential anti-DVT mechanism of PNS may involve the AGE-RAGE signaling pathway and the PI3K-Akt signaling pathway. Molecular docking presented a total of 10 binding interactions, with all molecules showing good binding ability with PNS-DVT common hub target genes (all binding energy <-6 kcal/mol). Analysis of clinical data showed that the combined use of PNS significantly reduced the incidence of postoperative DVT in patients undergoing orthopedic surgery compared with the use of low-molecular-weight heparin alone, which is the most commonly used clinical anticoagulant.