Senescence, a hallmark of mammalian aging, is associated with the onset and progression of cardiovascular disease. Angiotensin II (Ang II) signaling and zinc homeostasis dysfunction are increased with age and are linked to cardiovascular diseases, but the relationship among these processes has not been investigated. We previously reported that Ang II as well as zinc overload increase reactive oxygen species (ROS) leading to increased senescence. NADPH oxidases produce ROS that are involved in normal function; however, overproduction of ROS by these enzymes is associated with vascular dysfunction and disease. Aortic VSMCs express Nox1 and Nox4, but Nox1, which produces mainly superoxide mediates the growth promoting effects of Ang II. Further, production of ROS by Nox1 is associated with senescence and atherosclerosis. In this study, we tested the hypothesis that zinc-induced senescence is mediated by activation of Nox1. We found that zinc increases Nox1, but not Nox4 protein expression, an effect that was prevented by TPEN, a zinc chelator. Further, downregulation of Nox1 by siRNA, but not Nox4, prevented Ang II-, as well as zinc-induced senescence. These data suggest that zinc homeostasis dysfunction may accelerate the development of atherosclerosis by a Nox1-dependent mechanism.