The abnormal blood vessels in tumor sites, causing poor tumor perfusion and hypoxia environment, restrict the chemodynamic therapy (CDT) potency significantly. To attain the synergistic therapy of tumor vascular normalization with CDT, herein, we constructed a dual-functional nanocatalyst with a simple structure, cuprous oxide by dextran (Cu2O@Dex), to restore proper tumor perfusion and tumor oxygenation. The in vitro experiment outcomes illustrated that Cu2O@Dex hardly releases Cu (Cu+/2+) under neutral conditions, which avoids unnecessary catalytic reaction in blood circulation. Under the weak acidic condition (pH 6.5), Cu2O@Dex begins to release Cu (Cu+/2+), catalyzing the nitric oxide (NO) generation for vascular normalization. Also, Cu2O@Dex further releases a large amount of Cu (Cu+/2+) under more acidic intratumor cells (pH 5.5), fast catalyzing the hydroxyl radical (center dot OH) generation for CDT. The in vivo experiment observations verified that Cu2O@Dex could improve tumor perfusion significantly 3 h post injection, which lasted for more than 144 h. The effective perfusion (Hoechst 33342+) area in the Cu2O@Dex group was 3.8-fold higher than that in the phosphate buffer saline (PBS) group after 48 h of injection, confirming the effectiveness of Cu2O@Dex to induce vascular normalization. Noticeably, tumor vascular normalization further enhanced the therapeutic effect of CDT through delivery of H2O2 generator juglone (JUG) more smoothly. The antitumor efficacy of Cu2O@Dex plus JUG was 86.5% with no obvious toxicity. Overall, our design achieved the dual-catalytic effects integrated in one simple nanostructure for tumor vascular normalization-enhanced CDT.