Oligodendroglioma is an important type of lower-grade glioma (LGG), which is a slowly progressing brain tumor. Many LGGs eventually transform into a more aggressive or malignant type. Enhanced angiogenesis is a characteristic of malignantly transformed oligodendroglioma (m-oligodendroglioma). However, the pathogenesis and signaling pathways associated with angiogenesis and proliferation in m-oligodendroglioma are not well understood. In this study, we identified that Insulin Gene Enhancer Protein (ISL2) and its angiogenic capacity were inversely related to survival according to LGG patient data from an online database, and this was further confirmed with pathological LGG patient samples, including malignantly transformed samples, by detecting the expression of ISL2, the angiogenic markers vascular endothelial growth factor (VEGFA) and CD31 and the proliferation marker Ki-67. We then established novel oligodendroglioma patient tumor-derived orthotopic xenograft mouse models and cell lines to verify the role of ISL2 in regulating angiogenesis to promote oligodendroglioma growth and malignant transformation. Furthermore, ISL2 regulated ANGPT2 transcription by binding to the ANGPT2 promoter. Then, ANGPT2, a downstream gene, activated angiogenesis through VEGFA to promote oligodendroglioma malignant transformation. Finally, combining AAV-ISL2-shRNA with temozolomide suppressed oligodendroglioma progression more effectively than either monotherapy in vivo and in vitro. Thus, hypoxia-induced ISL2 regulated ANGPT2, which subsequently induced angiogenesis to promote oligodendroglioma growth and malignant transformation. Malignancy was accompanied by worsened hypoxia inside the tumor mass, creating a positive feedback loop. In conclusion, this study suggests that ISL2 is a biomarker for oligodendroglioma progression and that anti-ISL2 therapy may offer a potential clinical strategy for treating m-oligodendroglioma.