Adenosine triphosphate synthase (ATPS), an enzyme responsible for ATP generation, has been discovered on the surface of endothelial and tumor cells, where it serves as binding sites for angiostatin. This study explored a novel radioimmunotherapy strategy to target tumor angiogenesis in a follicular thyroid cancer model. We developed a radiopharmaceutical complex by labeling an anti-ATPS monoclonal antibody (mAb) with the radioisotope 177Lu using DOTA as a chelating agent. The 177Lu-DOTA-ATPS mAb demonstrated high labeling efficiency (99.0%) and stability in serum. Western blot analysis and confocal microscopy revealed ectopic ATPS expression on the membranes of FTC-133 cells. FTC-133 cells showed a significant higher cellular uptake of 177Lu-DOTA-ATPS mAb at 24 hr (186.2 ± 4.9%, p < 0.001) compared to that of baseline, which could be specifically blocked by unlabeled ATPS mAb (87.2 ± 2.8%, p < 0.05). In mice bearing a follicular thyroid cancer xenograft, 177Lu-DOTA-ATPS mAb accumulated significantly in tumors, with a tumor uptake of 12.9 ± 0.6%ID/g on day 4. This radioimmunotherapy strategy led to substantial tumor growth inhibition (TGI) after 4 weeks of treatment (77.6% compared to controls, p < 0.05). Furthermore, combining 177Lu-DOTA-ATPS mAb with sunitinib, an anti-angiogenic drug, enhanced the therapeutic efficacy of sunitinib in the mouse model (TGI = 70.9% vs. 40.0%). Our study successfully developed 177Lu-DOTA-ATPS mAb, a radioimmunotherapy agent targeting tumor blood vessels. This approach shows significant promise for inhibiting tumor growth, both as a single therapy and in combination with other anti-cancer drugs in thyroid cancer.