Thyroid cancer is the most common endocrine malignancy. A multitargeted tyrosine kinase inhibitor, lenvatinib, has been used for the treatment of advanced thyroid cancer. To elucidate the mechanism of resistance to lenvatinib in thyroid cancer cells, we established lenvatinib‐resistant sublines and analyzed the molecular mechanisms of resistance. Two thyroid cancer cell lines (TPC‐1 and FRO) were used, and resistant sublines for lenvatinib (TPC‐1/LR, FRO/LR) were established. In TPC‐1/LR, the phosphorylation of epidermal growth factor receptor (EGFR), extracellular signal‐regulated kinase (ERK), and Akt was enhanced whereas in FRO/LR, the phosphorylation of EGFR and downstream signal transduction molecules was not enhanced. The addition of epidermal growth factor decreased sensitivity to lenvatinib in TPC‐1 and FRO. The combination of EGFR inhibitors lapatinib and lenvatinib significantly inhibited the growth of TPC‐1/LR in both in vitro and mouse xenograft models. Short‐term exposure to lenvatinib enhanced the phosphorylation of EGFR in six thyroid cancer cell lines regardless of their histological origin or driver gene mutations; however, phosphorylation of ERK was enhanced in all cells except TPC‐1. A synergistic growth‐inhibitory effect was observed in three thyroid cancer cell lines, including intrinsically lenvatinib‐resistant cells. The results indicate that signal transduction via the EGFR pathway may be involved in the development of lenvatinib resistance in thyroid cancer cells. The inhibition of the EGFR pathway simultaneously by an EGFR inhibitor may have therapeutic potential for overcoming lenvatinib resistance in thyroid cancer. This study elucidates the mechanism of lenvatinib‐resistance in thyroid cancer cells. We demonstrated that the strategy to inhibit the EGFR pathway simultaneously by an EGFR inhibitor might have therapeutic potential for overcoming lenvatinib‐resistance in thyroid cancer.