Abstract: Liver sinusoidal endothelial cells (LSECs) are the largest non-parenchymal cell population in the liver. As the first line of defense for peripheral blood entering the liver, LSECs actively maintain the homeostasis of liver sinusoidal microenvironment under physiological conditions. In the pathological states, LSECs are abnormally activated by other cells in the hepatic sinuses and peripheral immune cells, regulating the occurrence and progression of liver diseases through various ways. Numerous studies have shown that mitigating the dysfunction of LSECs is an effective strategy for the clinical treatment of acute and chronic liver diseases. This article reviews the role of LSECs in liver diseases and introduces the research on related therapeutic drugs, aiming to provide insights and reference for elucidating the pathogenesis of liver diseases and developing clinical therapeutic approaches.