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Anaplastic thyroid cancer (ATC) is a rare but severe form of thyroid cancer responsible for approximately 50% of thyroid cancer deaths. Consequently, the identification of innovative therapies remains crucial for the effective treatment of ATC. Molecular radiotherapy is a rapidly growing field within oncology, and the cell surface antigen CD44v6, which is overexpressed in several cancers, is a plausible target for molecular radiotherapy of ATC. IHC of 39 patient samples with ATC was evaluated for CD44v6 expression. Biodistribution and dosimetry of iodine-125 (¹²⁵I)–/lutetium-177 (¹⁷⁷Lu)–labeled UU-40, a CD44v6-specific antibody, followed by in vivo efficacy in two ATC xenograft models with varying target expression levels (ACT-1 and BHT-101), accompanied by single-photon emission computed tomography (SPECT) imaging, evaluated radiolabeled UU-40 for therapeutic efficiency in ATC xenografts. The IHC revealed CD44v6 immunoreactivity in 46% of patient samples with ATC. The biodistribution favored ¹⁷⁷Lu-labeled UU-40 over the ¹²⁵I-labeled antibody and confirmed the in vivo specificity of both radioconjugates. The in vivo efficacy and accompanied SPECT imaging of a moderate CD44v6-expressing xenograft model (BHT-101) verified the tumor specificity, as well as the target-specific effect of ¹⁷⁷Lu-labeled UU-40 on tumor growth and survival. A 100% complete response rate was demonstrated as a result of therapy using a single dose of 16 MBq ¹⁷⁷Lu-labeled UU-40 in a high CD44v6-expressing xenograft model (ACT-1), and SPECT imaging revealed excellent tumor uptake of the radioconjugate at 14 days after injection. This study verifies the expression of CD44v6 in ATC and strengthens the superiority and promise of ¹⁷⁷Lu-labeled UU-40 over ¹³¹I-labeled UU-40 for antibody-based molecular radiotherapy of CD44v6-positive ATC.