Neuropeptide Y (NPY) has been linked to the initiation and progression of breast cancer. NPY activates six G-protein coupled receptors (GPCRs) in breast cancer, of which, NPY1R and NPY5R are the most biologically significant. Activation of these receptors by peptide binding impacts tumour proliferation, migration, invasion, and angiogenesis, especially in hypoxia. Here we show that the use of NPY1R and NPY5R antagonists in MDA-MB-231 and MCF7 breast cancer lines can inhibit hallmarks of cancer and that NPYRs are associated with hypoxic regions in tumour samples. These overlaps correlated with adverse outcomes. Breast cancer is the second most common cancer, with more than 1.3 million people diagnosed each year. Therefore, a greater understanding of how NPY1R and NPY5R antagonists impact breast cancer cell migration, proliferation, invasion, and formation, with a focus on hypoxia, will be an asset in the development of novel therapeutics for breast carcinomas.