Objectives. Existing evidence produces conflicting findings regarding the effect of sesame intake on inflammatory biomarkers; this knowledge gap has yet to be met through systematic review and meta-analysis. This meta-analysis of randomized, controlled clinical trials (RCTs) was conducted to evaluate the effects of sesame consumption on markers of inflammation in humans. Methods. PubMed, Scopus, and the Cochrane Database of Systematic Reviews were searched through August 2020 to identify relevant papers for inclusion. Using the random-effects model, data were evaluated as weighted mean differences (WMD) with 95% confidence intervals (CI). Cochrane’s Q and I-squared (I2) tests were used to identify within-studies heterogeneity. Results. Seven RCTs with 310 participants (157 intervention and 153 control) were included in the meta-analysis. Sesame consumption reduced serum level interleukin-6 (IL-6) (WMD − 0.90; 95% CI (−1.71, −0.09), I2 = 80.4%) compared to the control group. However, sesame intake had no significant effects on C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) compared to the control group. Subgroup analysis identified a reduction in serum CRP, TNF-α, and IL-6 concentration among studies with participants who had a higher level of these biomarkers at baseline, those which used sesamin capsules, and those with a bigger sample size, those conducted in Asia, and studies on females. Conclusion. Sesame consumption reduced serum levels of IL-6 but did not affect CRP and TNF-α in humans. Additional trials should be conducted utilizing a larger and longer treatment duration, along with studies using different sesame formulations (capsule, oil, and seed) and conducting on participants with varied health conditions.