This study is to prepare and evaluate Pluronics-modified mixed micelle (MM) to deliver polyphenolic myricetin (MYR) across the blood-brain barrier. MYR has been proven to be an effective anticancer agent against glioblastoma cells in our previous studies. However, the poor solubility of MYR limits its access to the brain. In this study, the feasibility of preparing lipid-based MM that combined sodium dodecyl sulphate (SDS) with Pluronic F68 (F68) and Labrasol was investigated. Furthermore, the nonionic surfactant coating technology for the protection of MYR against oxidation, and its attainment in oral bioavailability, was examined. On account of the altered biomaterial properties of F68/SDS–modified lipid-based micelles, myricetin-loaded mixed micelles (MYR-MMs) were prepared by solvent-evaporation method to self-assembly into MMs. The average size of MYR-MMs was 96.3 nm, with negatively charged potential and spherical in shape. The drug loading of MYR-MMs was high with the increased grafting ratio, the more prolonged drug release profile, and more effective killing glioblastoma cells in vitro. Moreover, MYR-MMs showed a higher preference for the brain than free MYR alone, suggesting the novel MMs loaded with MYR could promote absorption and increase relative bioavailability. Taken together, the F68/SDS–modified and Labrasol-modified lipid-based micelles may provide a promising method to deliver polyphenolic compounds across the brain to treat brain tumor.