Growing evidence indicates that a small number of cancer cells express stem cell markers and possess stem cell-like properties that promote malignant progression. Sex-determining region Y-box2 (SOX2) is a stem cell transcription factor essential for maintaining the properties of cancer stem cell (CSC). As CSC properties have been associated with angiogenesis and vasculogenic mimicry (VM), we aimed to comprehensively investigate whether SOX2 regulates CSC properties, angiogenesis, and VM in colorectal carcinoma (CRC) and its potential mechanism in this study. For this study, sphere formation assay, flow cytometry, cell survival analysis, tube formation, 3D culture, immunoblot, mouse model, and luciferase reporter assay were performed in vivo and in vitro. Expressions of SOX2 and miR-450a-5p in CRC tissue samples were examined through immunohistochemistry. First, the expression of SOX2 was not only associated with poor differentiation and prognosis but also promoted angiogenesis and VM. Knockdown of SOX2 ceased stemness properties, angiogenesis, and VM, along with decreased expression of CD133, CD31, and VE-cadherin as observed in functional experiments. Downregulation of SOX2 was found to inhibit tumorigenesis in vivo. Second, miR-450a-5p suppressed the expression of SOX2 by targeting its 3'UTR region directly and hence restrained SOX2-induced CSC properties, angiogenesis, and VM. Moreover, SOX2 overexpression preserved the miR-450a-5p-induced inhibition of CRC properties, angiogenesis, and VM. Finally, clinical samples exhibited a negative correlation between miR-450a-5p and SOX2. Patients with higher SOX2 and lower miR-450a-5p expressions had a poorer prognosis than patients with inverse expressions. Conclusively, we elucidated a unique mechanism of miR-450a-5p-SOX2 axis in the regulation of stemness, angiogenesis, and VM, which may act as a potential therapeutic practice in CRC.