Objective <p>Major depressive disorder (MDD) is accompanied by prominent physiological abnormalities, notably sleep disturbances and immune-inflammatory dysregulation. As a serotonin-norepinephrine reuptake inhibitor, antidepressant duloxetine exhibits both anti-inflammatory effects and therapeutic benefits in improving sleep architecture. This study aimed to investigate the effects of duloxetine on objective sleep parameters and serum pro-inflammatory cytokine levels in patients with MDD, and further to explore the correlation between treatment-related improvements in sleep quality and dynamic changes in inflammatory cytokine profiles.</p> Methods <p>This study included 74 patients with MDD who met the DSM-5 criteria, had a baseline 24-item Hamilton Depression Rating Scale score ≥ 20, and no prior use of antidepressants or anti-inflammatory drugs within 3 months. All patients were administered duloxetine at a daily dose of 40–60&#xa0;mg for 4 consecutive weeks. Objective sleep parameters, including total sleep time (TST), sleep efficiency (SE), wake time after sleep onset (WASO), and rapid eye movement (REM) latency, were evaluated using polysomnography (PSG). Serum levels of 6 pro-inflammatory cytokines, including interleukin‑1β (IL‑1β), IL‑6, IL‑8, IL‑12, tumor necrosis factor‑α (TNF‑α), and interferon‑γ (IFN‑γ), were measured by enzyme-linked immunosorbent assay. Changes from baseline to post-treatment were analyzed using paired <i>t</i>-tests or Wilcoxon signed-rank tests based on data distribution. Correlation analyses were performed using Pearson or Spearman tests, followed by partial correlation analysis adjusting for potential confounders.</p> Results <p>After 4 weeks of duloxetine treatment, significant improvements in sleep parameters were observed, characterized by increased TST (<i>t</i> = -6.614, <i>P</i> &lt; 0.001) and SE (<i>t</i> = -6.631, <i>P</i> &lt; 0.001), as well as decreased WASO (<i>t</i> = 6.331, <i>P</i> &lt; 0.001). Moreover, serum concentrations of IL‑1β (<i>t</i> = 4.759, <i>P</i> &lt; 0.001), IL‑8 (<i>t</i> = 6.327, <i>P</i> &lt; 0.001), IL‑12 (<i>t</i> = 6.194, <i>P</i> &lt; 0.001), and IFN‑γ (<i>t</i> = 8.713, <i>P</i> &lt; 0.001) were significantly reduced following treatment. Furthermore, at baseline, TST was negatively correlated with serum IL-12 levels (<i>r</i> = -0.306, <i>P</i> = 0.016) in patients with MDD. Similarly, SE was negatively correlated with serum levels of IL‑1β (<i>r</i> = -0.343, <i>P</i> = 0.006), IL‑8 (<i>r</i> = -0.297, <i>P</i> = 0.019), and IL‑12 (<i>r</i> = -0.279, <i>P</i> = 0.028). Additionally, following treatment, the change in TST was negatively correlated with the change in IL-12 levels (<i>r</i> = -0.285, <i>P</i> = 0.025). Likewise, the change in SE was negatively correlated with changes in IL-8 levels (<i>r</i> = -0.263, <i>P</i> = 0.039) and IL-12 levels (<i>r</i> = -0.294, <i>P</i> = 0.020).</p> Conclusions <p>Four-week duloxetine treatment was associated with improved sleep disturbances and reduced peripheral pro-inflammatory cytokine levels in patients with MDD. The baseline correlations between sleep parameters and pro-inflammatory cytokines, as well as the concurrent changes in these indicators following duloxetine treatment, reveal a potential relationship between sleep improvement and altered inflammatory profiles during duloxetine intervention. These preliminary findings suggest a possible link between duloxetine-related therapeutic effects on sleep and inflammatory regulation in MDD, which warrants further verification in future studies.</p>