Saffron is derived from a specific portion of the flowers of Crocus sativus L. and is one of the most expensive spices in the world. Besides its use in Mediterranean, Middle Eastern, and South Asian cuisines, it also has been a part of Ayurvedic and Persian traditional healing strategies for thousands of years. Recently, human studies have emerged examining the capacity of saffron or its individual bioactive phytochemicals to ameliorate conditions and symptoms related to, for example, depression, neurodegenerative conditions, and symptoms of diabetes and cardiovascular disease. This narrative review presents a summary of human studies assessing these and other potential health benefits of saffron supplementation and highlights issues for future research.