Epithelial cell adhesion molecule (EpCAM) is an important biomarker in tumors. In hepatocellular carcinoma (HCC), EpCAM + cells exhibit high invasiveness, tumorigenic ability, therapeutic resistance, and self-renewal ability, often identified as liver cancer stem cells (CSCs). Detecting EpCAM + cells in tumor lesions and circulation is valuable for predicting patient prognosis and monitoring therapeutic outcomes, emphasizing its clinical significance. Given its broad expression in HCC, especially in CSCs and circulating tumor cells (CTCs), EpCAM-targeting agents have garnered substantial research interest. However, the role of EpCAM in HCC progression and its regulatory mechanisms remains poorly understood. Furthermore, clinical applications of EpCAM, such as liquid biopsy and targeted therapies, are still controversial. This review summarizes the biological properties of EpCAM + HCC cells, explores the regulatory mechanisms governing EpCAM expression, and discusses its clinical significance of using EpCAM as a prognostic marker and therapeutic target.