Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death among women worldwide. Poor prognosis in breast cancer patients is often linked to the presence of intratumoral hypoxic areas caused by abnormal vascularization and insufficient oxygen availability, which results in energetic crisis in cancer cells; metabolic and epigenetic reprogramming; the transcription of genes involved in angiogenesis; cancer cell proliferation; increased motility, aggressiveness and metastasis; the accumulation of mutations; genomic instability; the maintenance of stem cell characteristics; stromal cell recruitment; extracellular matrix remodeling; chronic inflammation; immune evasion; and adaptive responses in the tumoral microbiota. Furthermore, hypoxia is often correlated with resistance to traditional antitumor treatments used alone or in combination, which results in the need to implement novel therapies to overcome or alleviate the negative effects of oxygen deprivation in breast cancer theranostics. In breast cancer modeling research, micro- and nanofabrication-based technologies, including breast cancer-on-chip and breast cancer metastasis-on-chip platforms, are able to recapitulate the metastatic cascade of breast cancer in different controlled oxygen gradients. Mass spectrometry-based proteomics, including mass spectrometry imaging, offers opportunities for detecting, quantifying and understanding the roles of proteins and peptides, protein-protein interaction networks, and posttranslational modifications of proteins involved in hypoxia-associated biopathological processes. In this mini-review, we have summarized several modern approaches that are able to overcome the undesirable effects of hypoxia for breast cancer treatment. Thus, natural compounds with inhibitory effects on hypoxia-related signaling pathways in breast cancer cells and the tumor microenvironment, hyperbaric oxygen therapy, viral vector-based therapy that uses genetically engineered oncolytic viruses, and oncological bacteriotherapy based on biohybrid platforms, including anaerobic bacteria that are able to colonize inaccessible hypoxic regions in breast tumors to deliver chemotherapeutic drugs just into the tumor site, and smart nanoplatforms for abundant O2 generation within hypoxic breast cancer areas, including erythrocyte-like nanoparticles, metal-organic framework-nanoparticles, or engineered microalgae-metal-organic framework oxygenators, have been designed to relieve tumor hypoxia, induce antitumor responses, and improve the effects of traditional anti-breast cancer therapies.