Gastrointestinal cancer is one of the most common cancers globally. Melatonin, a natural endogenous body hormone, has been of interest for years, due to its anti-cancer characteristics, such as antiproliferative, antimetastatic, and cytotoxic as well as apoptotic induction. Through regulating several proteins such as melatonin upregulated mRNAs and proteins of downregulated Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2), as well as cytoplasmic protein such as calcium-binding proteins calmodulin or tubulin, and nuclear receptors, including RORα/RZR, and acts by non-receptor-regulated mechanisms, melatonin can exert anti-cancer efficacy. Moreover, melatonin modulates angiogenesis by targeting mRNA and protein expression of endothelin-converting enzyme (ECE-1) protein. In the present review, we address in vivo, in vitro and clinical reports on its anti-cancer efficacies, and the molecular mechanisms of action responsible for these effects. We advance the possibility of therapeutic melatonin administration for cancer therapy.