Abstract: This study aimed to investigate the use of hybrid exosomal vesicles (RU-exos), prepared by fusing exosomes derived from U87 and RAW264.7 cells, as a delivery system for cannabidiol (CBD) to cross the blood–brain barrier (BBB) and target glioblastoma (GBM), thereby exerting antitumor effects through the regulation of mitophagy. The RU-exos@CBD formulation was characterized using transmission electron microscopy, dynamic light scattering, and zeta potential measurements. Intracellular reactive oxygen species (ROS) levels were measured using the DCFH-DA probe, changes in mitochondrial membrane potential (MMP) were assessed using the JC-1 probe, and the expression of mitophagy-related proteins was analyzed by Western blotting. In addition, an intracranial orthotopic GBM model was established in nude mice to evaluate the in vivo targeting ability, therapeutic efficacy, and biosafety of RU-exos@CBD. Immunohistochemistry (IHC) and immunofluorescence (IF) staining were performed to assess tumor cell proliferation. The results showed that RU-exos@CBD treatment induced intracellular ROS accumulation and decreased MMP, providing preliminary evidence for the induction of mitophagy. Further mechanistic studies demonstrated that RU-exos@CBD activated mitophagy by inhibiting the PI3K/AKT/mTOR signaling pathway. In vivo experiments confirmed that RU-exos@CBD effectively crossed the BBB and accumulated in tumor regions. Compared with free CBD, RU-exos@CBD significantly enhanced the inhibition of GBM proliferation. Hematoxylin and eosin (H&E) staining of major organs revealed no apparent pathological damage, indicating that RU-exos@CBD exhibited favorable biosafety and tissue compatibility.