Tumor necrosis factor (TNF) is a biomarker of inflammation whose levels are elevated in patients with several diseases associated with dysregulation of the immune response. The main limitations of currently used anti-TNF therapies are the induction of immunodepression, which in many cases leads to serious adverse effects such as infection and cancer, and the inability to cross the blood-brain barrier in neuroinflammatory conditions. Melatonin, in addition to being a chronobiotic compound, is widely known for its antioxidant and immunomodulatory capacity to control inflammatory processes in different pathological contexts. The aim of the present review is to address human-based studies that describe the effect of melatonin on TNF production. The review includes all the articles published in PubMed databases until April 15, 2024. After depuration, 45 studies were finally included in the review, 23 related to the in vitro action of melatonin in human cells and 22 in vivo studies in humans. Most of the data reviewed support the idea that melatonin has an immunosuppressive effect on TNF levels, which, together with its low toxicity profile, low cost, and ability to cross the blood-brain barrier, points to melatonin as a potential anti-TNF therapy. Therefore, improving our knowledge of the action of melatonin in regulating TNF through appropriate clinical trials would reveal the true potential of this molecule as a possible anti-TNF therapy.