Baicalein, a widely used Chinese herbal medicine, has been proved as a promising chemopreventive compound for many cancers. The aim of this work was to assess the anti-tumor effect of baicalein in the orthotopic glioma models. It was found that treatment of mice with U87 gliomas with baicalein (20 and 40 mg/kg/day, i.p.) significantly inhibited the intracerebral tumor growth and prolonged the survival. Furthermore, treatment with baicalein suppressed cell proliferation, promoted apoptosis, and arrested cell cycle in U87 gliomas. In addition, treatment with baicalein reduced tumor permeability, attenuated edema of tumors and brains, and improved tight junctions in gliomas. Finally, treatment with baicalein reduced the expression of HIF-1 alpha, VEGF, and VEGFR2 in U87 gliomas. In addition, treatment with baicalein also markedly suppressed tumor growth and prolonged the survival of rats with 9L gliomas. In conclusion, baicalein has an obvious anti-tumor activity in the orthotopic glioma models. Our results suggested that treatment with baicalein might be an effective therapy for recurrent malignant brain cancers through suppressing tumor growth and alleviating edema.