Lipid droplets (LDs) are dynamic organelles that store neutral lipids when energy is in excess and serve as an energy reservoir during energy deprivation. Altered hepatic lipid metabolism is a critical factor influencing the development of liver disease, such as viral hepatitis, fatty liver disease, and hepatocellular carcinoma. Perilipin 2 (PLIN2) is a protein associated with the metabolism of intracellular LDs and is closely related to the clinical outcome of liver disease. While the impact of PLIN2 on the pathogenesis of liver disease is gradually being recognized, the mechanism of action remains unclear. In this review, we highlight recent advances in the understanding of PLIN2's role in the pathogenesis of liver disease through LD biogenesis, LD contact sites, LD dynamics, and lipophagy. Furthermore, we discuss the current opportunities for PLIN2-targeted therapy for liver disease.