Despite the generally good prognosis of differentiated thyroid cancer (DTC), impairments in health-related quality of life (HRQoL) remain a major concern in these patients. This study examined the patterns and predictors of change in mental and physical HRQoL in DTC survivors following radiotherapy ablation. Two hundred patients with DTC who received radiotherapy ablation in southern Taiwan between 2015 and 2018 were interviewed using the Taiwan version of the 36-item Short-form Health Survey (SF-36), the Taiwanese Depression Questionnaire (TDQ), and the Hamilton Rating Scale for Anxiety (HAM-A) at baseline and after 24 and 48 weeks of treatment. The demographic characteristics, thyroid-related factors, recombinant human thyroid-stimulating hormone (rhTSH), and serum calcium level were also collected. Improvements in both mental and physical HRQoL were noted over the first 24 weeks following radiotherapy ablation. Between 24 and 48 weeks, mental HRQoL was increasing, whereas physical HRQoL decreased. Higher levels of anxiety and pain predicted both poor physical and mental HRQoL. Further, higher levels of depression predicted poor mental HRQoL. Additionally, factors such as low income, rhTSH use, elevated TSH levels, low free T4, and higher physical HRQoL were associated with poorer mental HRQoL during the follow-up period. The early detection and intervention of depression, anxiety, and pain should be the objective for programs aiming to improve HRQoL.