Saffron as a natural product has long been used to impede and treat different disorders including cardiovascular disease (CVDs). Stigma is the most principal part of saffron. Various compounds such as carotenoids and flavonoids are the essential components of saffron stigma. The health benefits of saffron have been shown in previous studies; however, there is a lack of comprehensive data on the mechanistic aspects of its cardiovascular-health properties. This current comprehensive review focuses on the medicinal applications of saffron, and then the new findings regarding its cardiovascular-health effects and various cellular and molecular mechanisms of action will be debated. The literature search of MEDLINE, Embase, PubMed, Google Scholar and Cochrane Library was performed for all comparative studies since 2000-2018 with the limitations of the English language. The results provided new evidence about antioxidant, anti-inflammatory, anti- atherogenic, anti- apoptotic, anti- hypertensive, and hypolipidemic effects of saffron. Pharmacological effects of saffron are due to a number of ingredients contained within this spice, including safranal, crocetin and crocins. Our study concludes that saffron with wide range of usefulness in medicine may be the potent candidate in the process of new drug production for the treatment of CVDs.