Abstract Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with unfavorable prognosis and 5-year survival. The purpose of this study was to investigate the underlying mechanisms involved in TNBC progression. We determined that CD24 expression was elevated in highly lung and lymph node metastatic TNBC cells. CD24 depletion inhibited primary tumor growth and lymph node and lung metastasis and reduced the number of blood and lymphatic vessels in the tumor microenvironment. CD24 knockdown impaired EGFR/Met-mediated signaling and reduced lymphangiogenesis- and angiogenesis-related molecules, including vascular endothelial growth factors A and C, by promoting EGFR and Met protein instability via the lysosomal degradation pathway. CD24 monoclonal antibody treatment reduced lung metastasis and prolonged the survival in a lung metastasis mouse model. Clinical analyses revealed that the CD24high/METhigh “double-positive” signature identified a subset of TNBC patients with worst outcomes. We conclude that CD24 could be a therapeutic target by itself and in combination with the Met expression could be a good prognostic biomarker for TNBC patients.