Liver sinusoidal endothelial cells (LSEC) are liver-specific endothelial cells. Under physiological conditions, LSECs exhibit open fenestrae, facilitating the efficient bidirectional exchange of small molecules between hepatocytes and blood. They are crucial for maintaining hepatic filtration and metabolic homeostasis, suppressing the activation of hepatic stellate cells (HSC), and modulating hepatic immune responses and tolerance, thereby forming the principal barrier of the liver microcirculation. During liver injury, however, LSECs undergo phenotypic changes—including capillarization, cellular senescence, and endothelial-to-mesenchymal transition. These changes result in increased intrahepatic vascular resistance, impaired transvascular exchange, and enhanced secretion of pro-angiogenic and pro-inflammatory factors. In the absence of timely intervention, this pathological cascade can exacerbate liver damage. Therefore, therapeutic targeting of LSEC dysfunction has emerged as a novel strategy for chronic liver disease. This article systematically elaborates on the dynamic changes and specific mechanistic roles of LSECs in both physiological homeostasis and chronic liver disease, summarizes current therapeutic strategies aimed at LSECs, and also discusses existing research limitations and suggests future directions.