BACKGROUND: Post-stroke depression (PSD) is a common neuropsychiatric complication after stroke. Neuroinflammation triggered by the stroke event may be its predisposing factor. METHODS: We systematically searched all electronic databases up to December 22, 2024. Observational studies comparing cytokine levels between PSD and non-PSD patients were included. Sensitivity analysis, subgroup analysis, and meta-regression were conducted to assess robustness, explore heterogeneity, and identify effect modifiers. RESULTS: A total of 26 studies with 6573 acute stroke patients were included, of whom 2453 developed PSD. PSD patients were older (63.7 vs. 62.8 years) and included more females (36.4 % vs. 35.1 %) than non-PSD patients. PSD patients had significantly higher serum levels of IL-1β (SMD = 0.35, 95 % CI = [0.07, 0.63], p = 0.02), IL-6 (SMD = 0.74, 95 % CI = [0.50, 0.97], p <
0.001), IL-18 (SMD = 0.49, 95% CI = [0.13, 0.86], p = 0.007), TNF-α (SMD = 0.44, 95 % CI = [0.15, 0.72], p = 0.003) and IFN-γ (SMD = 0.11, 95 % CI = [0.02, 0.19], p = 0.01), while IL-10 levels showed no significant difference (p = 0.06). IL-6 levels remained associated with PSD diagnosis at 1, 3 and 6 months. Meta-regression identified female proportion (IL-6: p = 0.043
IL-10: p = 0.024), mean age (IL-18: p = 0.015
TNF-α: p = 0.040), BMI (IL-18: p = 0.019), and diabetes proportion (IL-6: p = 0.009
TNF-α: p = 0.033) as significant moderators. CONCLUSIONS: Inflammatory cytokines may serve as biomarkers for PSD, offering insights into its pathophysiology and potential diagnostic tools. Prospero registration number: CRD42024548753.