Melatonin (MLT) is an endogenous hormone produced by pineal gland which possess promising anti-tumor effects. Anti-inflammatory and anti-oxidant properties of MLT, along with its immunomodulatory, proapoptotic, and anti-angiogenic properties, are often referred to the main mechanisms of its anti-tumor effects. Recent evidence has suggested that epigenetic alterations are also involved in the anti-tumor properties of MLT. Among these MLT-induced epigenetic alterations is modulation of the expression of several oncogenic and tumor suppressor microRNAs(miRNAs). MiRNAs are among the most promising and potential therapeutic and diagnostic tools in different diseases and enhanced the development of better therapeutic drugs. Suppression of oncomicroRNAs such as microRNA-21, - 20a, and - 27a as well as, up-regulation of microRNA-34 a/c are among the most important effects of MLT on microRNAs homeostasis. Recently, miR-21 has attracted the attention of scientists due to the its wide range of effects on different cancers and diseases. Regulation of this RNA may be a key to the development of better therapeutic targets. The present review will summarize the findings of in vitro and experimental studies of MLT-induced impacts on the expression of microRNAs which are involved in different models and numerous stages of tumor initiation, growth, metastasis, and chemo-resistance.