BACKGROUND: Ferroptosis-induced therapy is a promising approach for treating anaplastic thyroid carcinoma (ATC), a highly lethal form of cancer. However, the specific effects of two anti-angiogenic agents, lenvatinib and anlotinib, on ferroptosis in ATC are not well understood. METHODS: Methods: To investigate the anticancer activity of lenvatinib and anlotinib in vivo, a subcutaneous tumor model was established in mice. The pharmacological effects of these agents on ATC cells were assessed using various assays, including CCK-8, colony formation, transwell, and sphere-forming assays. Angiogenesis was evaluated using a tubule formation assay. Reactive oxygen species (ROS) levels were measured by flow cytometry, and levels of ferroptosis and endoplasmic reticulum (ER) stress were determined through western blot assays. Immunohistochemistry analyses were used to profile the expression of GPX4, HO-1, PERK, and CHOP in tumor tissues. RESULTS: Both lenvatinib and anlotinib demonstrated dose- and time-dependent inhibition of Luciferase-8505 C-induced subcutaneous tumors in mice, with anlotinib showing greater efficacy than lenvatinib. In vitro experiments revealed that while both drugs were effective at inhibiting angiogenesis, anlotinib displayed superior antitumor effects in terms of cell viability, proliferation, tumor sphere formation, migration, and invasion. Mechanistic studies indicated that anlotinib induced ROS-mediated ferroptosis through the ER stress pathway, a response not observed with lenvatinib treatment. CONCLUSION: Anlotinib showed superior efficacy in treating ATC compared to lenvatinib, independent of their anti-angiogenic properties. The ability of anlotinib to induce ER stress-mediated ferroptosis suggests that targeting ferroptosis may hold promise as a therapeutic strategy for ATC.