Citrulline, which is an important amino acid/protein in human metabolism and its biosynthesis and metabolic pathway has not been fully elucidated yet, is known as the end product of glutamine metabolism and arginine metabolite. The richest known source of citrulline is watermelon, and this amino acid is thought to have an important role in drought tolerance. Some possible mechanisms related to the pathways related to the metabolism of citrulline are explained, and the importance and place of metabolism in these pathways are tried to be understood. However, detailed data are needed to explain the extremely complex set of relationships. At the same time, citrulline taken as a supplement has an effect on diseases. The most well-known of these effects is on cancer and metabolic diseases. Because redox imbalance can be strongly associated with oxidative disorders, dietary antioxidants have an instrumental role in preventing many human diseases (cancer, atherosclerosis, stroke, neurodegeneration, and diabetes). Relatedly, iNOS is one of the three classes of NOS and is the most potent NO generator contributing to immune responses in certain types of cancer. Although studies on antioxidant and hypolipidemic effects in diabetic patients are scarce, it was concluded that CIT and watermelon extract can beneficially affect glycemic status and inflammation in diabetes mellitus.