Wheat is the major staple food in many diets. Based on the increase in worldwide mortality attributable to diet-related chronic diseases, there is an increasing interest in identifying wheat species with greater health potential, more specifically for improved anti-oxidant and anti-inflammatory properties. In particular, ancient varieties (defined as those species that have remained unchanged over the last hundred years) are gaining interest since several studies suggested that they present a healthier nutritional profile than modern wheats. This manuscript reviews the nutritional value and health benefits of ancient wheats varieties, providing a summary of all in vitro, ex vivo, animal and human studies that have thus far been published. Differences in chemical composition, and biochemical and clinical implications of emmer, einkorn, spelt, khorasan and various regional Italian varieties are discussed. Although many studies based on in vitro analyses of grain components provide support to the premise of a healthier nutritional and functional potential of ancient wheat, other in vitro studies performed are not in support of an improved potential of ancient varieties. In the light of existing evidence derived from in vivo experiments, the ancient wheat varieties have shown convincing beneficial effects on various parameters linked to cardio-metabolic diseases such as lipid and glycaemic profiles, as well as the inflammatory and oxidative status. However, given the limited number of human trials, it is not possible to definitively conclude that ancient wheat varieties are superior to all modern counterparts in reducing chronic disease risk.