ARTICLE ABSTRACTAnaplastic thyroid carcinoma (ATC) is a rare but aggressive undifferentiated tumor that frequently metastasizes to the brain. The multiple kinase inhibitor lenvatinib and sorafenib have been approved to treat unresectable differentiated thyroid cancer, and lenvatinib has been approved in Japan to treat ATC. This study compared the effects of lenvatinib and sorafenib in mouse models of central nervous system metastases of ATC. Immunodeficient mice were inoculated with ATC cells, and the effects of lenvatinib and sorafenib were evaluated in subcutaneous- and brain metastasis–mimicking models. Drug distribution was evaluated by imaging tandem mass spectrometry (ITMS). Neither lenvatinib nor sorafenib affected the viability of ATC cell lines, whereas both inhibited VEGF secretion by ATC cells. In the subcutaneous tumor model, both lenvatinib and sorafenib inhibited growth and were associated with reduced tumor microvessel density. In the brain metastasis–mimicking model, lenvatinib, but not sorafenib, inhibited the growth of ATC cells and reduced microvessel density in brain lesions. ITMS showed that lenvatinib was well-distributed in both subcutaneous and brain lesions, whereas the distribution of sorafenib was lower in brain than in subcutaneous lesions. These results demonstrate that lenvatinib is well-distributed in mouse models of ATC, and inhibited the growth of ATC brain lesions predominantly by inhibiting angiogenesis, suggesting that lenvatinib is highly potent against ATC brain metastases.