Targeting tumor angiogenesis is a potential therapeutic strategy for glioblastoma because of its high vascularization. Tivozanib is an oral pan-VEGF receptor tyrosine kinase inhibitor that hits a central pathway in glioblastoma angiogenesis. We conducted a phase II study to test the effectiveness of tivozanib in patients with recurrent glioblastoma. Ten adult patients were enrolled and treated with tivozanib 1.5 mg daily, 3 weeks on/1 week off in 28-day cycles. Brain MRI and blood biomarkers of angiogenesis were performed at baseline, within 24–72 h of treatment initiation, and monthly thereafter. Dynamic contrast enhanced MRI, dynamic susceptibility contrast MRI, and vessel architecture imaging were used to assess vascular effects. Resting state MRI was used to assess brain connectivity. Best RANO criteria responses were: 1 complete response, 1 partial response, 4 stable diseases, and 4 progressive disease (PD). Two patients were taken off study for toxicity and 8 patients were taken off study for PD. Median progression-free survival was 2.3 months and median overall survival was 8.1 months. Baseline abnormal tumor vascular permeability, blood flow, tissue oxygenation and plasma sVEGFR2 significantly decreased and plasma PlGF and VEGF increased after treatment, suggesting an anti-angiogenic effect of tivozanib. However, there were no clear structural changes in vasculature as vessel caliber and enhancing tumor volume did not significantly change. Despite functional changes in tumor vasculature, tivozanib had limited anti-tumor activity, highlighting the limitations of anti-VEGF monotherapy. Future studies in glioblastoma should leverage the anti-vascular activity of agents targeting VEGF to enhance the activity of other therapies.