Resection surgery is the first-line therapy for high-grade glioma that is performed in >70% of patients with glioblastoma, typically within days of suspected diagnosis. Current protocols for follow-on chemoradiotherapy have shown only modest efficacy in eliminating residual disease, leading to inevitable tumor recurrence. There remains a need for new approaches to swiftly and effectively treat post-operative residual disease to prevent the rapid early progression of glioblastoma. Using syngeneic preclinical models of glioblastoma resection, we identified spatially and temporally restricted windows of blood-brain barrier disruption localised to the resection margin, during the immediate (0h) and early (48-72h) postoperative periods. Intravenous administration of fluorescently labelled, clinically-used liposomal nanoparticles during these periods revealed selective accumulation at the postoperative resection margin, with minimal penetration into other regions of the brain with an intact blood-brain barrier. Immunohistological analysis confirmed nanoparticle extravasation within the margin parenchyma, largely interacting with microglial populations closely associated with residual tumor cells. Exploiting this, we performed intravenous administration of doxorubicin-loaded liposomes coinciding with the peaks of postoperative blood-brain barrier disruption and demonstrated both enhanced chemotherapy delivery to the brain and consequently inhibition of tumor recurrence from a single administration across two glioblastoma models. Overall, this work identifies therapeutically exploitable windows of postoperative blood–brain barrier disruption and demonstrates that appropriately coordinated timing can enable clinically-used liposomal nanomedicines to be repurposed for early postoperative therapy in aggressive brain tumors.