To illustrate the types and roles of skeletal muscle-derived bioactive molecules in mediating the communication from skeletal muscle to the heart and blood vessels. A systematic literature search was performed in four different databases. Eligible articles were screened using the inclusion and exclusion criteria. Two researchers independently performed literature screening and selection, data extraction and literature quality analysis. This study included 29 articles (2 clinical studies and 27 basic studies). Data analysis of the included studies revealed that skeletal muscle synthesizes and releases abundant extracellular vesicles (EVs), myokines (FSTL1, FNDC5/irisin and others) and microRNAs (miRNA-126 and others) to mediate the communication from skeletal muscle to the heart and blood vessels. Certain skeletal muscle-derived EVs, myokines and miRNAs were found to enhance cardiac function, reduce cardiac fibrosis and inhibit cardiac injury, and improve apoptosis and inflammation. In the blood vessels, these bioactive molecules stimulated angiogenesis, improved endothelial cell function, protected against vascular stiffness, and attenuated atherosclerosis and neointimal hyperplasia. Notably, IL-10, FSTL1, b-FGF, VEGF, irisin, musclin, myonectin, exo-miRNA26a, and miRNA-126 definitely played protective roles in the heart and blood vessels through interorgan communication. Skeletal muscle synthesizes and releases EVs, myokines and miRNAs, which mediate the communication from skeletal muscle to the heart and blood vessels. The majority of these bioactive molecules are associated with cardiovascular protective effects. And they may provide new targets for more in-depth mechanism and clinical researches of communication from skeletal muscle to the heart and blood vessels.