Objective This study aimed to design a standard method of psychological intervention and evaluate the effect of such psychological intervention against the psychological distress of differentiated thyroid cancer (DTC) patients in the treatment with radioactive iodine. Methods The enrolled patients were randomly divided into the intervention group and the control group. Both the patients in the 2 groups received the routine nursing care, while the patients in the intervention group also received the additional standard psychological interventions. The questionnaires including patient health questionnaire-9 (PHQ-9), generalized anxiety disorder 7-item (GAD-7), cancer fatigue scale (CFS) and positive and negative affect schedule (PANAS) were used to assess psychological status. These questionnaires were performed at week 0 (T0), week 8 (T1, immediately after the last time of intervention) and week 24 (T2, 16 weeks after the intervention). Results PHQ-9, GAD-7, CFS and Negative Affect (NA) scores measured at T1 and T2 in the intervention group were significantly lower than those in the control group ( P < 0.001). And intervention group also had higher positive affect (PA) scores at T1 and T2 ( P < 0.001). Furthermore, the changes of PHQ-9, GAD-7, CFS, PA and NA scores from T0 to T1 and T0 to T2 were more evident in the intervention group than in the control group. Conclusion Psychological intervention could significantly improve psychological distress of DTC patients in the treatment with radioactive iodine.