Dexamethasone is a fluorinated steroid and a synthetic member of glucocorticoids. It is an approved medication for inflammatory and allergic disorders. Also, it is clinically used in high doses to manage pain associated with metastatic osteolytic lesions. Furthermore, it has a wide array of side effects, particularly at high doses and after prolonged consumption, like; hypertension, hyperglycemia, and dyslipidemia. It is a promising tool for studying the underlying mechanisms of metabolic syndrome and insulin resistance. This review article discusses metabolic syndrome and insulin signaling. In addition, this review article will discuss metabolic-dexamethasone effects on the skeletal muscle, liver, adipose tissue, pancreas, brain, and the cardiovascular system, its underlying mechanisms of action, and the benefits of use, in comparison to the other dietary and chemical models of insulin resistance and type 2 diabetes, to identify new potential pharmacological treatments of the metabolic syndrome and its related complications.