Abstract The angiopoietin (Ang)–Tie pathway has been intensely pursued as candidate second‐generation anti‐angiogenic target. While much of the translational work has focused on the ligand Ang2, the clinical efficacy of Ang2‐targeting drugs is limited and failed to improve patient survival. In turn, the orphan receptor Tie1 remains therapeutically unexplored, although its endothelial‐specific genetic deletion has previously been shown to result in a strong reduction in metastatic growth. Here, we report a novel Tie1 function‐blocking antibody (AB‐Tie1‐39), which suppressed postnatal retinal angiogenesis. During primary tumor growth, neoadjuvant administration of AB‐Tie1‐39 strongly impeded systemic metastasis. Furthermore, the administration of AB‐Tie1‐39 in a perioperative therapeutic window led to a significant survival advantage as compared to control‐IgG‐treated mice. Additional in vivo experimental metastasis and in vitro transmigration assays concurrently revealed that AB‐Tie1‐39 treatment suppressed tumor cell extravasation at secondary sites. Taken together, the data phenocopy previous genetic work in endothelial Tie1 KO mice and thereby validate AB‐Tie1‐39 as a Tie1 function‐blocking antibody. The study establishes Tie1 as a therapeutic target for metastasis in a perioperative or neoadjuvant setting.