Purpose: The objective is to investigate psychological status and quality of life (QoL) using Hospital Anxiety and Depression Scale (HADS) and Short-Form (36) Health Survey (SF-36) questionnaires in patients with proven differentiated thyroid cancer (DTC) who are referred for radioactive iodine (RAI) ablation before, during, and after treatment. Methods: Of patients who underwent total thyroidectomy with a pathologically proven DTC (papillary and follicular types) referred for RAI treatment to our department in 2018, 150, in whom the diagnosis was newly established, were referred for the first course of RAI treatment and were consecutively enrolled in the study. The patients received an oral dose of radioiodine (3700 or 5550 MBq). For evaluation of anxiety, depression, and QoL, all patients are given two standard questionnaires, HADS, and SF-36 and are requested to answer them at four time points. First one was at 1 month before RAI, second was at the time of RAI treatment. Third and fourth ones were 1 week and 6 months later, respectively. Results: The mean age of patients was 39.17 (±12.95) years and 121 (80.7%) were female and 29 (19.3%) were male. Values of HADS and SF-36 scores at corresponding time points were significantly correlated using Pearson correlation (HADS and SF-36 scores at 1 month before RAI: r = −0.56, P < 0.001; at time of RAI: r = −0.71, P < 0.001; 6 months after RAI: r = 0.19, P = 0.021). Using paired-sample t -test, for HADS, except for difference between time points of 1 month before RAI and time of RAI, pairwise difference between scores of other time points was statistically significant after Bonferroni correction. For SF-36, pairwise difference between scores of all three time points was statistically significant. Interaction of age, gender, RAI dose, and thyroid-stimulating hormone level at the time of RAI on HADS and SF-36 scores did not show statistical significance. Conclusion: Trend in scores over several-months’ time discloses gradual improvement of QoL and merits close observation but limited psychiatric intervention.