Brain tumors are difficult to target and treat. The blood-brain barrier (BBB) limits drug delivery to pathological sites, and standard mono-chemotherapy typically results in suboptimal efficacy and development of drug resistance. We here set out to load a synergistic drug combination in polymeric micelles, and combined them with ultrasound- and microbubble-mediated BBB opening in glioma models in mice. Via high-throughput screening of various chemotherapy combinations in different glioma cell lines, valrubicin and panobinostat were identified as a synergic drug combination and co-loaded in mPEG-b-p(HPMAm-Bz)-based polymeric micelles. Intravenous administration of double-drug micelles showed good tolerability and resulted in significant tumor growth inhibition in mice with subcutaneous GL261 gliomas. In orthotopically inoculated patient-derived HSJD-DIPG-007 diffuse intrinsic pontine gliomas, notoriously known to have an intact BBB and poor drug responsiveness, we provide initial experimental evidence showing that multidrug micelles plus sonopermeation can help to improve treatment efficacy. Our work exemplifies that synergistic drug combinations can be efficiently co-loaded in polymeric micelles, and that advanced nanosonochemotherapy combination regimens hold promise for the treatment of hard-to-treat brain tumors.