Purpose: Much of the volume of solid tumors typically exists in a chronically hypoxic microenvironment that has been shown to result in both chemotherapy and radiation therapy resistance. The purpose of this study was to use localized microbubble delivery to overcome hypoxia prior to therapy. Materials and Methods: In this study, surfactant-shelled oxygen microbubbles were fabricated and injected intravenously to locally elevate tumor oxygen levels when triggered by noninvasive ultrasound in mice with human breast cancer tumors. Changes in oxygen and sensitivity to radiation therapy were then measured. Results: In this work, we show that oxygen-filled microbubbles successfully and consistently increase breast tumor oxygenation levels in a murine model by 20 mmHg, significantly more than control injections of saline solution or untriggered oxygen microbubbles (P<.001). Using photoacoustic imaging, we also show that oxygen delivery is independent of hemoglobin transport, enabling oxygen delivery to avascular regions of the tumor. Finally, we show that overcoming hypoxia by this method immediately prior to radiation therapy nearly triples radiosensitivity. This improvement in radiosensitivity results in roughly 30 days of improved tumor control, providing statistically significant improvements in tumor growth and animal survival (P<.03). Conclusions: Our findings demonstrate the potential advantages of ultrasound-triggered oxygen delivery to solid tumors and warrant future efforts into clinical translation of the microbubble platform. (C) 2018 Elsevier Inc. All rights reserved.