Background: Lenvatinib, a tyrosine kinase inhibitor (TKI) recently approved for treating radioactive iodine-refractory differentiated thyroid cancer, has been shown to delay disease progression and provide meaningful benefit for overall survival (OS). However, there is no predictive marker for response to lenvatinib before initiating treatment. We comprehensively analyzed clinical and radiological parameters to predict response to lenvatinib using lesion-based assessments. Methods: Medical records were collected from 67 patients treated with lenvatinib in 11 referral hospitals across Korea from June 2015 to December 2017. Up to 96 measurable lesions, defined as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, were evaluated serially until progressive disease (PD) occurred, and tumor doubling time (TDT) was calculated based on changes between historical computed tomography (CT) scans and baseline CT scans performed at treatment initiation. Results: Excluding patients with anaplastic thyroid cancer, no thyroidectomy, nontarget lesions only, or treatment periods of <1 month, 57 patients were analyzed, of whom 7 (12.2%) were TKI-naive. The median progression-free survival was 5.1 months (95% confidence interval [CI], 4.4-9.5), the median OS was 19.3 months (95% CI 12.4-not reached), the mean duration of response was 6.0 ± 4.4 months, and the objective response rate was 38%. In lesion-based assessments, 31 lesions (32.2%) with significant tumor shrinkage (complete remission or partial response) were significantly associated with shorter TDT (<12 months; p = 0.02). Patients with rapidly PD with a shorter initial TDT (<6 months) were more likely to respond to lenvatinib (p = 0.03). Patients exposed to lenvatinib at an average of ≥16 mg per day, or who were TKI-naive before treatment with lenvatinib, had a lower risk of progression; however, the risk reduction did not reach statistical significance (daily dosage p = 0.07, TKI exposure p = 0.09). Conclusions: TDT calculations at the beginning of treatment and lesion-based tumor assessment may help identify potential responders to lenvatinib therapy and predict therapeutic responses.