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Background: The etiology of depression involves many biological and environmental factors, among which the inflammatory process is an important contributor. However, the role of pro-inflammatory cytokines in postmenopausal depression is unclear. Therefore, we aimed to explore the association between the serum concentrations of four pro-inflammatory cytokines (IL-1β, IL-6, IL-18, and TNF-α) and depressive symptoms in postmenopausal women who had been receiving menopause hormone therapy (MHT) for at least 6 months and postmenopausal women who had not received MHT. Methods: This study included a total of 136 Chinese postmenopausal women aged 40 to 65 years who visited the gynecology outpatient department between June 2020 and December 2022. They were divided into the POST group (n = 94) and the POST + MHT (n = 42) group. Demographic information was collected, and the Hamilton Rating Scale for Depression (HAMD) was used to assess depression. The circulating levels of IL-1β, IL-6, IL-18, and TNF-α were determined using ELISA kits. Results: According to the HAMD score, 39.36% of the participants in the POST group and 14.29% in the POST + MHT group were considered to have depression. The POST + MHT group had significantly lower serum concentrations of IL-18 and TNF-α than the POST group. Multiple linear regression analysis showed that the serum IL-18 (β = 3.996, 95% CI = 0.508–7.484), and TNF-α levels (β = 4.784, 95% CI = 0.939–8.629) were significant predictors of the HAMD-24 scores in women in the POST group. In addition, age was found to be positively related with the level of depression (β = 0.531, 95% CI = 0.063–0.999). Conclusions: Postmenopausal women who received MHT had a lower HAMD-24 score as well as lower serum TNF-α and IL-18 levels than women who did not receive MHT. Further, the TNF-α and IL-18 level were positively associated with the HAMD-24 score in women who had not received MHT. [ABSTRACT FROM AUTHOR]