Abstract: Bone metastasis is the primary cause of mortality in breast cancer (BC) patients. The present study elucidates the functional role of the differentiated embryonic chondrocyte-expressed gene 1 (DEC1) in promoting BC-related bone metastasis. Analysis of patient-derived samples and public databases revealed a significant upregulation of DEC1 and CXCR4 in breast tumors compared with adjacent normal tissues, with elevated levels correlating with increased metastatic potential, suggesting their synergistic involvement in BC progression. Intracardiac injection experiments demonstrated that Dec1-WT 4T1 cells induced more severe osteolysis and larger metastatic lesions than Dec1-KD 4T1 cells. In MDA-MB-231 cells, DEC1 overexpression (OE) upregulated CXCR4 and proliferation/migration-related genes, whereas DEC1 knockdown reversed these effects. Notably, AMD3100, a specific CXCR4 antagonist, partially reversed the DEC1-OE-induced upregulation of CXCR4 and associated pro-metastatic genes. Mechanistically, DEC1 bound to the CXCR4 promoter region (−230 to −326) and activated its transcription, corroborated by ChIP-seq data. Furthermore, pharmacological inhibition of AKT (LY294002) or JAK2 (AZD1480), but not ERK (PD98059), attenuated DEC1-mediated CXCR4 upregulation, although all three inhibitors mitigated DEC1-driven migration-related gene expression. Additionally, DEC1 enhanced CXCL12 secretion from mesenchymal stromal cells and osteoblasts, amplifying the CXCR4/CXCL12 axis within the bone microenvironment. Collectively, our findings demonstrate that DEC1 promotes BC bone metastasis by directly transactivating CXCR4 expression, providing a molecular basis for targeting DEC1 to prevent and treat BC bone metastasis.