As an inevitable biological process, cardiovascular aging is the greatest risk factor for cardiovascular diseases (CVDs). Sestrin 2 (Sesn2), a stress-inducible and age-related protein associated with various stress conditions, plays a pivotal role in slowing this process. It acts as an anti-aging agent, mainly through its antioxidant enzymatic activity and regulation of antioxidant signaling pathways, as well as by activating adenosine monophosphate-activated protein kinase and inhibiting mammalian target of rapamycin complex 1. In this review, we first introduce the biochemical functions of Sesn2 in the cardiovascular aging process, and describe how Sesn2 expression is regulated under various stress conditions. Next, we emphasize the role of Sesn2 signal transduction in a series of age-related CVDs, including hypertension, myocardial ischemia and reperfusion, atherosclerosis, and heart failure, as well as provide potential mechanisms for the association of Sesn2 with CVDs. Finally, we present the potential therapeutic applications of Sesn2-directed therapy and future prospects.Copyright © 2020. Published by Elsevier B.V.