Sestrin2 (Sesn2), a highly conserved antioxidant protein, is induced by various stresses, including oxidative and energetic stress, and protects cells against those stresses. In normal physiological conditions, redox-homeostasis plays an essential role in cell survival and performs the cellular functions to protect the cells against oxidative damage. The liver is susceptible to oxidative stress, since it is responsible for xenobiotic detoxification and energy metabolism. For this reason, oxidative stress is associated with the pathogenesis of liver diseases. Recently, the role of Sesn2 has been investigated in liver injury and related diseases. In this paper, we review the role of Sesn2 in the pathophysiology of liver diseases and the potential clinical applications of Sesn2 as a therapeutic target to prevent/treat liver diseases. This article promotes our understanding of liver disease progression and advances the development of strategies for pharmacological intervention.