BACKGROUND: One of the important mechanisms of depression is long-term high levels of inflammation. Exercise may help relieve depressive symptoms and is associated with anti-inflammatory effects. This research methodically assesses how various exercise modalities influence peripheral inflammatory markers in individuals with depression, so that more personalized and precise exercise schemes can be provided for people with depression to improve inflammation. METHODS: Randomized controlled trials on depressive disorder, exercise, and inflammation published until May 2025 were screened in five databases. The Cochrane Risk of Bias tool (RoB2.0) was used to evaluate potential biases, with random effects meta-analyses gauging the impact of varying exercise regimens on peripheral inflammatory markers (CRP, IL-6 and TNF-alpha) involving exercise types, intensity, frequency, and length. Meta-regression analyses were employed to show the sources of heterogeneity and investigate potential moderator variables influencing CRP, IL-6, and TNF-alpha (PROSPERO CRD42024590612). RESULTS: A total of 13 unique studies with 1004 participants were included. Overall, exercise training could alleviate depressive symptoms (SMD -0.59, 95% CI -0.86 to -0.32, I2 61.7%, p < 0.001), and subgroup analysis showed that exercise lasting 8 to 12 weeks could reduce the level of TNF-alpha (MD -0.74, 95% CI -1.30 to -0.17, I2 0, p < 0.05). Apparent discrepancies between subgroup and meta-regression findings were resolved by advanced modeling, which identified a significant non-linear relationship for TNF-alpha (quadratic term p = 0.003), characterized by a reduction peak at 8 to 12 weeks followed by a gradual increase, rather than a positive linear trend. CONCLUSIONS: Exercise could alleviate depressive symptoms in individuals with depression. However, the influence of exercise length on TNF-alpha levels has conflicting conclusions because of inconsistent evidence and substantial heterogeneity. Future high-quality trials with standardized biomarker measurements and better control of confounding factors are essential to determine whether the antidepressant effects of exercise are mediated by inflammation.

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