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Glioblastoma (GBM), the deadliest primary brain malignancy, resists treatment because of the blood‒brain barrier (BBB) and intrinsic resistance mechanisms. Fluorescein (FL), a clinically approved fluorophore, shows promise as a sonosensitizer for sonodynamic therapy (SDT), but faces challenges in tumor delivery and incomplete mechanistic understanding beyond ROS-mediated damage. We developed a bioinspired platelet-based delivery platform exploiting the natural tumor-homing properties of platelets for targeted FL delivery. Platelets were loaded with fluorescein diacetate (FDA), a lipophilic prodrug that is converted intracellularly to active FL, combined with probenecid to inhibit MRP1-mediated efflux, generating the ultrasound-responsive FL@plt. In vitro, FL demonstrated sonocytotoxicity; upon low-intensity ultrasound, FL@plt rapidly released FL into GBM cells, producing significant cytotoxicity enhanced by probenecid-mediated retention. In subcutaneous and orthotopic mouse models, intravenous FL@plt with probenecid and sequential ultrasound achieved extensive tumor FL accumulation, massive necrosis, significant growth inhibition, and prolonged survival. Mechanistically, FL-SDT induces DNA damage while promoting HIF-1α degradation via the ubiquitin‒proteasome and autophagy‒lysosome pathways, thus suppressing downstream DNA repair enzymes (SMUG1 and LIG4). This dual mechanism combines direct genotoxicity with impaired DNA repair capacity, underlying the potent anti-GBM efficacy. Our platelet-based FL delivery represents a practical, safe, translational therapy for overcoming BBB limitations by disabling HIF-1α-regulated DNA repair.