This feasibility study evaluated the psychological status of patients with differentiated thyroid cancer (DTC) before, during, and 40 days after administration of I-131 radionuclide therapy (RAI). We investigated the appropriateness of providing patient a comprehensive psychological assessment in an isolation ward. Thirty consecutive patients (Study Group; SG) who received RAI were enrolled. The tools used were the Hospital Anxiety and Depression Scale (HADS) at three different moments, and the Coping Responses Inventory (CRI) at baseline for each patient. A supportive approach was also implemented. Data were collected at the first specialist visit, at the day of admission, and at 40 days follow-up visit. A matched cohort of patients (Control Group; CG), who did not receive psycho-oncological counseling, was retrospectively studied only about their medical needs and requests. Staff exposure to radiation was also compared during SG and CG hospitalization, to assess a possible reduction of radiological risk for them. A significant difference between the basal, intermediate, and final psychological status was observed (p < 0.0001), which was found to be irrespective of the induced hypothyroidism. Patients showed a significant worsening of their status in terms of anxiety and depression after the consent, but it improved 40 days after treatment. Repeated measures analysis showed a similar trend in patients’ psychological status over this period. At hospital discharge, patients showed indirect signs of increased well-being. CG required more nursing and medical interventions. Staff exposure was significantly lower during hospitalization of SG as compared to CG. This study demonstrates that timed psychological evaluation and appropriate support may help to reduce anxiety and depression of patients receiving a diagnosis of cancer and undergoing RAI. Moreover, an improvement of workplace safety was recorded.