Focused ultrasound-stimulated microbubble (MB + FUS) therapy is a promising radiation enhancement strategy, utilizing vascular disruption to enhance radiation efficacy. However, its mechanistic effects in large tumour volumes and clinical translatability remain insufficiently characterized. This study evaluates the synergistic impact of MB + FUS combined with radiation therapy (XRT) in a large-scale, immunosuppressed rabbit xenograft model using a clinically adaptable, MRI-guided 6144-element focused ultrasound (MRgFUS) system. Tumours were treated with MB + FUS, XRT, or both, with real-time image-guided MB activation and evaluation of treatment effects on vascular integrity, proliferation, and cellular stress responses. Assessments included Power Doppler ultrasound, histology, and immunohistochemistry targeting TUNEL, ASMase, Ki-67, Factor VIII, HIF-1α, and VEGF. Combination therapy induced significant vascular collapse, reduced perfusion, and decreased Factor VIII expression, alongside increased nuclear condensation, TUNEL positivity, and ASMase expression, consistent with ASMase-mediated endothelial apoptosis and vascular disruption. Upregulation of HIF-1α and VEGF indicated hypoxia-driven angiogenic signalling, while Ki-67 suppression reflected sustained tumour growth inhibition. Although immune responses were limited by host immunosuppression, the larger tumour burden provided clinically relevant constraints. The MRgFUS platform enabled precise and reproducible MB activation, reinforcing MB + FUS as a potent radio-enhancement modality. These findings support the continued development of MB + FUS toward clinical translation and highlight its potential as a complementary strategy to radiation therapy.