The aging of the global population has resulted in a significant increase in the incidence of stroke, disability, and mortality. Findings from numerous studies suggest that ROS generated during ischemic reperfusion are crucial in subsequent tissue damage. However, the role of nuclear factor-erythroid 2-related factor 2 (Nrf2), which regulates endogenous antioxidative functions, in pathological models of aging is not well understood. Our previous study showed that epicatechin (EC) upregulated brain Nrf2 expression in 2-month-old rats and reduced oxidative stress in cerebral ischemia-reperfusion injury (CIRI). In the present study, EC was administered to a 12-month-old rat model of CIRI (induced by middle cerebral artery occlusion and reperfusion) and a senescent SH-SY5Y cell model subjected to oxygen glucose deprivation/reoxygenation. EC treatment improved cerebral morphology and function; increased p-Nrf2 expression and unclear transportation and HO-1, SOD, and GSH expression; and reduced infarct volume and apoptosis in senescent rats. Moreover, EC enhanced cellular activity and the expression of p-Nrf2, HO-1, and NQO-1 while decreasing the ROS and MDA levels and mitigating apoptosis in senescent SH-SY5Y cells. These effects were attenuated upon si-Nrf2 introduction. The findings of this study offer novel insights into stroke prevention and therapy as well as drug development for the elderly population.