The Mediterranean Diet (MedDiet) has been promoted as a means of preventing and treating cardiodiabesity. The aim of this study was to answer a number of key clinical questions (CQs) about the role of the MedDiet in cardiodiabesity in order to provide a framework for the development of clinical practice guidelines. A systematic review was conducted to answer five CQs formulated using the Patient, Intervention, Comparison, and Outcome (PICO) criteria. Twenty articles published between September 2013 and July 2016 were included, adding to the 37 articles from the previous review. There is a high level of evidence showing that MedDiet adherence plays a role in the primary and secondary prevention of cardiovascular disease (CVD) and improves health in overweight and obese patients. There is moderate-to-high evidence that the MedDiet prevents increases in weight and waist circumference in non-obese individuals, and improves metabolic syndrome (MetS) and reduces its incidence. Finally, there is moderate evidence that the MedDiet plays primary and secondary roles in the prevention of type 2 diabetes mellitus (T2DM). The MedDiet is effective in preventing obesity and MetS in healthy and at-risk individuals, in reducing mortality risk in overweight or obese individuals, in decreasing the incidence of T2DM and CVD in healthy individuals, and in reducing symptom severity in individuals with T2DM or CVD.