Syndecan-4 (SDC4), a heparan sulfate proteoglycan, is aberrantly expressed in breast cancer and plays a significant role in tumor progression by influencing cell proliferation and promoting invasive growth. This study aimed to characterize its role in the tumor microenvironment by analyzing the contribution of SDC4 to vasculogenic mimicry (VM) and angiogenesis in human breast cancer cells. We silenced SDC4 in the triple-negative breast cancer (TNBC) cell lines MDA-MB-231, MDA-MB-468, and SUM-149 and analyzed its functions in vitro. SDC4 knockdown inhibited the VM of MDA-MB-231 cells as analyzed by fluorescence microscopy. Moreover, RT-qPCR revealed decreased expression of KLF4, EGR1, and HPSE, factors involved in VM, proangiogenic and pro-invasive processes in all TNBC cell lines. Western blotting revealed a partially cell-line-dependent regulation of these proteins by SDC4. At the functional level, SDC4 knockdown also impaired angiogenesis, decreasing the number of nodes and meshes in a 3D co-culture model comprising endothelial cells and TNBC cells. Using a Proteome Profile Human Angiogenesis Array, we observed that SDC4 knockdown decreased the secretion of VEGF and IGFBP-1, while it increased the secretion of IL-8, uPA, and amphiregulin in the conditioned media of the MDA-MB-231 and MDA-MB-468 co-cultures. Independent RT-qPCR analyses of gene expression were consistent with those of the angiogenesis array. Overall, these findings highlighted the crucial role of SDC4 in regulating both vasculogenic mimicry and angiogenesis in TNBC cells. The data indicate that SDC4 acts as a crucial regulatory molecule and represents a promising target for therapeutic strategies in breast cancer.