To investigate the relationship between fatigue and thyroid hormone levels in middle-aged and elderly patients with depression. Methods: Total 122 cases of middle-aged and elderly patients with depression were enrolled and divided according to the presence or absence of fatigue symptoms into the fatigue group (n=68) and non-fatigue group (n=54). In addition, 65 healthy volunteers who underwent physical examination at our hospital served as the control group (n=65). The age, first episode, suicidal behavior, and other general conditions of the patients were collected, and fasting blood samples of the three groups were taken to detect serum FT3, FT4, and TSH levels for comparison and analysis. Results: FT3 in the fatigue group was significantly lower than that in the non-fatigue group and control group (P<0.05). FT4/FT3 in the fatigue group was significantly higher than that in the non-fatigue group and control group (P<0.05). There was no difference in thyroid hormone levels between middle-aged and elderly patients in the fatigue group (P>0.05). Conclusion: There is an abnormality in thyroid hormone levels in middle-aged and elderly patients with depression who present fatigue symptoms, and this abnormality may be related to the disease state.