〔Abstract〕 Objective To explore the clinical significance of changes in serum leptin levels in patients with depression. Methods Sixty depression patients and 30 recruited healthy volunteers admitted to Shandong Daizhuang Hospital from January 2020 to December 2020 were selected as the research subjects. Depression patients were treated with conventional oral antidepressant drugs for 4 weeks according to their condition. The severity of depression symptoms before and after treatment was evaluated using the Hamilton depression scale (HAMD). The serum leptin levels of healthy volunteers and depression patients before and after treatment were measured using enzyme-linked immunosorbent assay (ELISA), and the changes in serum leptin levels of depression patients were analyzed. Results (1) The HAMD score of depression patients after treatment was lower than that before treatment, and the total effective rate of 100.00 %. (2) The levels of leptin in patients with depression before treatment were significantly higher than those in healthy volunteers, and the levels of leptin after oral antidepressant treatment were significantly higher than those before treatment, with statistical significance (P < 0.01). (3) The comparison of leptin levels between different genders showed that female leptin levels were higher than male leptin levels in the same group and time, and the differences were statistically significant (P < 0.01). Conclusion (1) Serum leptin levels in patients with depression are higher than those in healthy individuals, and serum leptin levels further increase after oral antidepressant treatment. (2) The serum leptin levels of women in healthy individuals and patients with depression are higher than those of men in corresponding states.