Diabetes mellitus is a metabolic disorder diagnosed by elevated blood glucose levels and a defect in insulin production. Blood glucose, an energy source in the body, is regenerated by two fundamental processes: glycolysis and gluconeogenesis. These two processes are the main mechanisms used by humans and many other animals to maintain blood glucose levels, thereby avoiding hypoglycaemia. The released insulin from pancreatic β-cells activates glycolysis. However, the glucagon released from the pancreatic α-cells activates gluconeogenesis in the liver, leading to pyruvate conversion to glucose-6-phosphate by different enzymes such as fructose 1,6-bisphosphatase and glucose 6-phosphatase. These enzymes' expression is controlled by the glucagon/ cyclic adenosine 3′,5′-monophosphate (cAMP)/ protein kinase A (PKA) pathway. This pathway phosphorylates cAMP-response element-binding protein (CREB) in the nucleus to bind it to these enzyme promoters and activate their expression. During fasting, this process is activated to supply the body with glucose; however, it is overactivated in diabetes. Thus, the inhibition of this process by blocking the expression of the enzymes via CREB is an alternative strategy for the treatment of diabetes. This review was designed to investigate the association between CREB activity and the treatment of diabetes and diabetes complications. The phosphorylation of CREB is a crucial step in regulating the gene expression of the enzymes of gluconeogenesis. Many studies have proven that CREB is over-activated by glucagon and many other factors contributing to the elevation of fasting glucose levels in people with diabetes. The physiological function of CREB should be regarded in developing a therapeutic strategy for the treatment of diabetes mellitus and its complications. However, the accessible laboratory findings for CREB activity of the previous research still not strong enough for continuing to the clinical trial yet.