Malignant brain tumors remain difficult to treat with chemotherapy because the blood–brain barrier (BBB) limits the amounts of potent agents that can reach the tumor, such that the drugs are unable to reach therapeutic dosage. Although various targeted carriers that encapsulate chemotherapeutic agents have been shown to improve drug delivery to brain tumors, the BBB is still a major obstacle in the use of chemotherapy for the treatment of these tumors. Human glioblastoma-bearing mice were injected intravenously with doxorubicin (Dox) encapsulated in atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes or unconjugated liposome. These treatments took place with or without BBB disruption induced by transcranial pulsed high-intensity focused ultrasound (pulsed HIFU). This study showed that the treatment with Dox encapsulated in AP-1-conjugated liposomes followed by pulsed HIFU enhanced the accumulation of the cytotoxic drug in cells and inhibited the growth of brain tumors in vivo. Combining pulsed HIFU with cytotoxic agents might improve their efficacy in patients with brain tumors while simultaneously reducing the drug side effects. Further investigation is required to provide a comprehensive physical characterization of the sonication process and to determine its bioeffects.