Epidemiological or in vitro evidence suggests a potential role for flavonoids as anti-inflammatory agents; we investigated the effect of flavonoids-rich foods or supplements on tumor necrosis factor- alpha (TNF-α) and interleukin-6 (IL-6) in long-term placebo-controlled human intervention trials. From 110 human intervention studies selected (MEDLINE, EMBASE, CHORANE, and FSTA databases), 32 long-term placebo-controlled trials were suitable for meta-analysis. After sensitivity analysis, seven studies imputed of bias were excluded and 25 studies were analyzed (TNF-α, n = 2404; IL-6, n = 2174). Levels of TNF-α decreased after flavonoid consumption in the fixed model only (mean difference (MD) (95% CI): −0.098 (−0.188, –0.009), p = 0.032), but metaregression results showed that neither higher dose, nor a longer duration of intervention were associated with a greater effect size. Subgroup analysis did not reveal any significant effect for quercetin and soy, but other sources (red wine, pomegranate, and tea extracts) showed a significant effect size both in fixed (MD (95% CI): TNF-α −0.449 (−0.619, –0.280), p < 0.001; IL-6 −0.346 (−0.612, –0.079), p = 0.011) and random (MD (95% CI): TNF-α −0.783 (−1.476, –0.090), p = 0.027; IL-6, −0.556 (−1.062, –0.050), p = 0.031) effect models. High-quality placebo-controlled trials are needed in order to identify flavonoids as the active ingredients.