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Background and Aims: Anti‐angiogenic therapies prolong patient survival in some malignancies but not glioblastoma. We focused on the relationship between the differentiation of glioma stem like cells (GSCs) into tumor derived endothelial cells (TDECs) and, anti‐angiogenic therapy resistance. Especially we aimed to elucidate the mechanisms of drug resistance of TDECs to anti‐angiogenic inhibitors and identify novel anti‐angiogenic drugs with clinical applications. Results: The mouse GSCs, 005, were differentiated into TDECs under hypoxic conditions, and TDECs had endothelial cell characteristics independent of the vascular endothelial growth factor (VEGF) pathway. In vivo, inhibition of the VEGF pathway had no anti‐tumor effect and increased the percentage of TDECs in the 005 mouse model. Novel anti‐angiogenic drugs for glioblastoma were evaluated using a tube formation assay and a drug repositioning strategy with existing blood–brain barrier permeable drugs. Drug screening revealed that the antidepressant sertraline inhibited tube formation of TDECs. Sertraline was administered to differentiated TDECs in vitro and 005 mouse models in vivo to evaluate genetic changes by RNA‐Seq and tumor regression effects by immunohistochemistry and MRI. Sertraline reduced Lama4 and Ang2 expressions of TDEC, which play an important role in non‐VEGF‐mediated angiogenesis in tumors. The combination of a VEGF receptor inhibitor axitinib, and sertraline improved survival and reduced tumor growth in the 005 mouse model. Conclusion: Collectively, our findings showed the diversity of tumor vascular endothelial cells across VEGF and non‐VEGF pathways led to anti‐angiogenic resistance. The combination of axitinib and sertraline can represent an effective anti‐angiogenic therapy for glioblastoma with safe, low cost, and fast availability. [ABSTRACT FROM AUTHOR]