Reactive oxygen species (ROS) are the metabolites of oxygen that plays a significant role in cell signaling and homeostasis. Under normal conditions, ROS formation is stabilized by various antioxidant defense systems (ROS scavengers). Several studies in both in-vitro and in-vivo models, together with clinical data indicated that increased production ROS and oxidative stress plays a crucial role in the development and progression of endothelial dysfunction. The interactions between the main cellular sources of ROS, such as mitochondria and NADPH oxidases, however, remain unclear. The purpose of this review is to outline various sources of ROS and describe the crosstalk between NADPH oxidase and mitochondria. Further, we will discuss different antioxidants that lower ROS production and ROS-induced pathological conditions such as aging, atherosclerosis, diabetes, hypertension, and degenerative neurological disorders. In this review, we have mainly focused on antioxidants that inhibit NADPH oxidase and mitochondrial sources of ROS. Moreover, the modification of antioxidants (targeted therapy) may be a significant approach for management of oxidative stress induced pathophysiological complications.