Purpose <p>this study aims to screen Protease-activated receptor 1 (PAR1) inhibitory active components with low bleeding side effects from anti-thrombin phytochemicals in <i>Polygonum amplexicaule</i> D. Don <i>var. sinense</i> Forb (PAF) to achieve multi-pathway antithrombosis without disrupting platelet hemostasis.</p> Methods <p>Docking simulation and platelet aggregation test were used to investigate interaction of PAR1-ligands to screen out anti-PAR1 active ingredients. FeCl₃-induced carotid artery (CA) thrombosis and inferior vena cava (IVC)-ligated thrombosis model were constructed to collect thrombi to weigh. Histopathological analysis, coagulation function, and hemorheological indicator detection of administered rats were conducted to analyze antithrombotic effectiveness and mechanism of these compounds, which were injected in tail veins of mice to evaluate bleeding side effects.</p> Results <p>Three promising ligands (epigallocatechin gallate, homoorientin, and myricetin) with strong affinity of PAR1 were selected from PAF. Epigallocatechin gallate and homoorientin showed antithrombotic effects with decreased bleeding tendency based on activity validation, suggesting that they may be prospective and effective candidate compounds of PAR1 antagonists.</p> Conclusion <p>the integrative strategy applied to these active components allowed to rapidly discover compounds with reducing bleeding side effects during thrombus treatment, providing valuable references for precisely targeted therapy and mechanism exploration of medicinal plants.</p>