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Background and objectives Glioblastoma is the most aggressive primary adult central nervous system of malignancy, with a median overall survival of 12-18 months. Recurrence is almost inevitable and carries poor outcomes, with median overall survival of 2-9 months and progression-free survival of 1.5-6 months. Treatment options are limited, as locoregional therapies apply to selected patients, and systemic treatments are restricted by the blood-brain barrier. Focused ultrasound has emerged as a noninvasive method to transiently and reversibly increase blood-brain barrier permeability. This study aims to systematically evaluate the clinical efficacy and safety of focused ultrasound-mediated blood-brain barrier modulation to enhance drug delivery in recurrent glioblastoma. Methods A systematic search of PubMed, ScienceDirect, Scopus, the Cochrane Library, ClinicalTrials.gov, and Wiley Online Library identified studies published between 2015-2024. The review followed PRISMA guidelines, with risk of bias assessed using ROBINS-I and protocol registration in PROSPERO (CRD420251010548). Disagreements were resolved by consensus. Results Twelve clinical trials involving 841 patients met inclusion criteria. Focused ultrasound-mediated platforms included SonoCloud-1, SonoCloud-9, ExAblate Neuro, and NaviFUS, with 1-10 sonication sessions lasting 2.5-22 min. blood-brain barrier opening was achieved in 68-100% of procedures. Median overall survival ranged from 9.95-18 months and median progression-free survival (PFS) from 2.2-3.5 months. Several studies reported improved outcomes vs historical chemotherapy-only controls, including progression-free survival-6 rates of 42-52%. Adverse events were mostly mild and transient, with >85% graded as Grade 1 and no treatment-related mortality. Interpretation and conclusions Focused ultrasound-mediated blood-brain barrier modulation is a practical therapeutic adjunct that improves intracerebral drug penetration and might extend survival beyond traditional outcomes; providing a noninvasive approach suitable for patients where systemic dose escalation is limited by toxicity and access.