AbstractOmega-3 fatty acids are potential anti-inflammatory agents that may exert beneficial outcomes in diseases characterised by increased inflammatory profile. The purpose of this study was to comprehensively evaluate the existing research on the effectiveness of n-3 fatty acid supplementation in lowering levels of circulating inflammatory cytokines in patients with heart failure (HF). From the beginning until October 2022, randomised controlled trials (RCTs) were the subject of PubMed, Scopus, Web of Science, and Cochrane Library literature search. Omega-3 fatty acid supplementation vs. placebo were compared in eligible RCTs to see how they affected patients with HF in terms of inflammation, primarily of tumour necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), and c-reactive protein (CRP). A meta-analysis employing the random effects inverse-variance model and standardised mean differences was performed to assess group differences. Ten studies were included in this systematic review and meta-analysis. Our main analysis (k = 5) revealed a beneficial response of n-3 fatty acid supplementation on serum TNF-a (SMD: − 1.13, 95% CI: − 1.75– − 0.50, I² = 81%, P = 0.0004) and IL-6 levels (k = 4; SMD: − 1.27, 95% CI: − 1.88– − 0.66, I² = 81%, P < 0.0001) compared to placebo; however, no changes were observed in relation to CRP (k = 6; SMD: − 0.14, 95% CI: − 0.35–0.07, I² = 0%, P = 0.20). Omega-3 fatty acid supplementation may be a useful strategy for reducing inflammation in patients with HF, but given the paucity of current studies, future studies may increase the reliability of these findings.