Adaptive resistance to vascular endothelial growth factor (VEGF)–targeted therapies occurs frequently among cancer patients. To investigate the underlying mechanisms, we established an array of orthotopic mouse models of ovarian cancer with adaptive resistance to anti-VEGF antibodies (AVAs). Genomic profiling showed an important role of endothelial p130cas in AVA resistant tumors. AVA treatment induced internalization of a p130cas/VEGFR2/TNKS1BP1 (a tankyrase-1–binding protein) complex in endothelial cells and initiated cell death and autophagy; knockdown of LC3B or caspase-10 reversed cells’ resistance to AVA treatment. Targeting host p130cas reduced the growth of AVA-resistant orthotopic ovarian tumors. Genomic ablation of vascular p130cas in p130casflox/floxTie2Cre mice significantly prolonged survival of mice carrying syngeneic ovarian tumors with adaptive resistance to AVA therapy. In ovarian cancer patients, higher p130cas expression in tumor-associated vasculature was associated with higher mortality. Collectively, these findings have important implications to guide future therapeutic strategies to overcome resistance to anti-angiogenic therapy.