Globally, cardio-cerebrovascular diseases (CCVDs) are the leading cause of death, and thus the development of novel strategies for preventing and treating such diseases is in urgent need. Traditional Chinese medicine (TCM), used for thousands of years in Asia and other regions, has been proven effective in certain disorders. As a long-time medicinal herb in TCM, Ginkgo biloba leaves (GBLs), have been widely used to treat various diseases including CCVDs. However, the underlying molecular mechanisms of medicinal herbs in treating these diseases are still unclear. Presently, by incorporating pharmacokinetic prescreening, target fishing, and network analysis, an innovative systems-pharmacology platform was introduced to systematically decipher the pharmacological mechanism of action of GBLs for the treatment of CCVDs. The results show that GBLs exhibit a protective effect on CCVDs probably through regulating multiple pathways and hitting on multiple targets involved in several biological pathways. Our work successfully explains the mechanism of efficiency of GBLs for treating CCVDs and, meanwhile, demonstrates that GDJ, an injection generated from GBLs, could be used as a preventive or therapeutic agent in cerebral ischemia. The approach developed in this work offers a new paradigm for systematically understanding the action mechanisms of herb medicine, which will promote the development and application of TCM.