Triple negative breast cancer (TNBC) is an invasive and metastatic phenotype of breast cancer with limited treatment options. Published studies have demonstrated an inhibitory effect of HIF-α inhibition by its inhibitor YC-1 (lificiguat) on growth and angiogenesis of TNBC. However, the underlying mechanism remains poorly understood. In the current paper, our results show that HIF-1α inhibitor significantly inhibited TNBC growth by increasing cellular apoptosis and decreasing MVD, independent of a cell-autonomous mechanism in both endothelial and tumor cells. Genetic screening and in vivo experiments showed that a large number of M2-polarized TAMs accumulated in the hypoxic peri-necrotic region (PNR), where placental growth factor (PlGF) and its ligand, vascular endothelial growth factor receptor-1 (VEGFR-1) were upregulated. Furthermore, YC-1 skewed the polarization of TAMs away from M2 to M1 phenotype, therefore inhibiting TNBC angiogenesis and growth. This effect was further abrogated by VEGFR-1 neutralization and TAM depletion following clodronate liposome injection. These findings provide preclinical evidence for an indirect mechanism underlying YC-1-induced suppression of TNBC growth and angiogenesis, thereby offering a treatment option for TNBC.