Diabetes mellitus type 2 (T2DM) has been a global health problem. Current studies have shown that the increased mortality and morbidity in T2DM are related to vascular complications. The vascular complications were caused by increased reactive oxygen species (ROS) associated with chronic hyperglycemia and insulin resistance. The increase of ROS in T2DM was influenced by the p38 MAPK pathway which is directly related to the modulation of nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) of endothelium cells. The decrease of NO by eNOS also has a connection with an event known as eNOS uncoupling. The decrease of eNOS plays a role in the pathogenesis of T2DM and its vascular complications such as increased inflammatory pro-cytokine, activation of NADPH pathway, increased of AGEs, VCAM-1, ICAM-1, and also the activation of protein kinase c and Rho-kinase pathway. Some interventions indirectly or directly have modulated NO relayed to its work targets such as oral antidiabetic drugs (metformin, sulfonylurea, and acarbose) or some polyphenol compounds such as emodin, α-Lipoic acid, curcumin, and olive oil. Modulation of NO in these interventions can be strong evidence that NO can be a target for further therapy in the management of T2DM and its complications. Keywords: eNOS, vascular complication, Type 2 Diabetes mellitus.