Chronic inflammation contributes to multiple diseases including cardiovascular diseases, autoimmune disorders, metabolic disorders, and psychiatric conditions. Melatonin, a hormone responsible for circadian rhythm, plays a complex role within the immune system, including having an anti-inflammatory effect. While there are numerous animal studies demonstrating this effect, few human clinical trials have been conducted. This systematic review of clinical trials examined whether exogenous melatonin reduces levels of inflammatory markers in humans. We searched PubMed, Embase, Cochrane Library, Scopus, and PsycINFO, and the references of the identified articles for randomized and non-randomized placebo-controlled trials. Data were extracted from the articles and meta-analyses were conducted using a random effects model to calculate standardized mean differences (SMDs, i.e., Cohen's d). From an initial search result of 4548 references, 31 studies met the inclusion criteria and were included involving 1517 participants. Melatonin had significant anti-inflammatory effects on interleukin (IL)-1 (SMD -1.64; 95% confidence interval [CI] -2.86, -0.43; p = 0.008), IL-6 (-3.84; -5.23, -2.46; p < 0.001), IL-8 (-21.06; -27.27, -14.85; p < 0.001), and tumor necrosis factor (TNF) (-1.54; -2.49, -0.58; p = 0.002), but not on C-reactive protein (CRP) (-0.18; -0.91, 0.55; p = 0.62). Trimming outlier studies with large effect sizes eliminated publication bias, and summary effect sizes were significant for IL-1 (SMD -1.11; 95% CI -1.90, -0.32; p = 0.006), IL-6 (-1.91; -2.98, -0.83; p = 0.001), and IL-8 (-13.46; -18.88, -8.04; p < 0.001), but not for TNF (-0.45; -1.13, 0.23; p = 0.19). Exogenous melatonin reduced levels of inflammatory markers and may be useful for prevention and adjuvant treatment of inflammatory disorders. Melatonin is safe with few side effects, which makes it an excellent agent for prevention of inflammatory disorders. Because chronic inflammation increases with aging and inflammation plays a role in the etiology of numerous diseases that affect older populations, melatonin has the potential to be widely used particularly in older adults.