CD73 is an ecto‐nucleotidase overexpressed in various types of tumors that catabolizes the generation of extracellular adenosine, a potent immunosuppressor. We and others have shown that targeted blockade of CD73 can rescue anti‐tumor T cells from the immunosuppressive effects of extracellular adenosine. Another important function of extracellular adenosine is to regulate adaptive responses to hypoxia. However, the importance of CD73 for tumor angiogenesis and the effect of anti‐CD73 therapy on tumor angiogenesis remain unknown. In this study, we demonstrated that CD73 expression on tumor cells and host cells contribute to tumor angiogenesis. Our data revealed that tumor‐derived CD73 enhances the production of vascular endothelial growth factor (VEGF) by tumor cells that host‐derived CD73 is required for in vivo angiogenic responses and that endothelial cells require CD73 expression for tube formation and migration. Notably, the pro‐angiogeneic effects of CD73 relied on both enzymatic and non‐enzymatic functions. Using a mouse model of breast cancer, we demonstrated that targeted blockade of CD73 with a monoclonal antibody significantly decreased tumor VEGF levels and suppressed tumor angiogenesis in vivo. Taken together, our study strongly suggests that targeted blockade of CD73 can significantly block tumor angiogenesis, and further supports its clinical development for cancer treatment. What's new? The pro‐tumorigenic nucleotidase CD73, a potential therapeutic target, plays a key role in the generation of the extracellular immunosuppressor adenosine. While its pro‐tumorigenic effects have thus far been attributed to adenosine‐mediated immunosuppression, this study shows that CD73 also promotes tumor angiogenesis via enzymatic and non‐enzymatic functions. Tumor levels of vascular endothelial growth factor (VEGF) were reduced and tumor angiogenesis suppressed in a breast cancer mouse model following treatment with a monoclonal antibody targeted against CD73. The findings highlight a previously unknown mechanism of action for anti‐CD73 therapy and further support its clinical development for cancer treatment.