Carthamus tinctorius L. is widely used in traditional Chinese medicines for the treatment of cardiovascular disease. However, our current understanding of the molecular mechanisms supporting its clinical application still lags behind. In this study, a systems pharmacology approach integrating drug-likeness evaluation, oral bioavailability prediction, target exploration, GO enrichment analysis, KEGG pathway performance and network construction was adopted to explore its therapeutic mechanism. A total of 21 active ingredients contained in Carthamus tinctorius L. and 113 major proteins were screened out as effective players in the treatment of cardiovascular disease through some related pathways. And the association among the active ingredients, major hubs and main pathways was investigated, implying the potential biological progression of Carthamus tinctorius L. acting on cardiovascular disease. Importantly, the majority of hubs and pathways were found to be highly related with platelet activation process. Core genes that can be regulated by Carthamus tinctorius L. in platelet activation pathway were PRKACA, PIK3R1, MAPK1, PPP1CC, PIK3CA and SYK, and they may play a central role in suppressing platelet aggregation. The systems pharmacology approach used in this study may provide a feasible tool to clarify the mechanism of traditional Chinese medicines and further develop their therapeutic potentials.