The epithelial-to-mesenchymal transition (EMT) is a critical process in carcinogenesis, characterized by the acquisition of motility, invasiveness, and resistance to chemotherapy and radiotherapy. Melatonin, a hormone produced by the pineal gland, has been shown to inhibit EMT in cancer progression. This review summarizes the current knowledge on how melatonin regulates key EMT-related markers, transcription factors, and microRNAs. Melatonin's actions on EMT are multifaceted, including its ability to inhibit the expression of EMT-related transcription factors such as Snail, Slug, ZEB1, ZEB2, and Twist1, as well as its effects on microRNA expression. The review highlights the potential of melatonin as an adjuvant to conventional cancer therapies due to its lack of toxic side effects and its ability to enhance drug efficacy. Additionally, melatonin's role in regulating signaling pathways involved in EMT, such as TGF-β, Wnt/β-catenin, Notch, IL6/STAT3, PI3/AKT, HH-GLI, and receptor tyrosine kinase signaling, is discussed. Overall, melatonin's inhibitory effects on EMT make it a promising candidate for enhancing cancer treatment outcomes.The epithelial-to-mesenchymal transition (EMT) is a critical process in carcinogenesis, characterized by the acquisition of motility, invasiveness, and resistance to chemotherapy and radiotherapy. Melatonin, a hormone produced by the pineal gland, has been shown to inhibit EMT in cancer progression. This review summarizes the current knowledge on how melatonin regulates key EMT-related markers, transcription factors, and microRNAs. Melatonin's actions on EMT are multifaceted, including its ability to inhibit the expression of EMT-related transcription factors such as Snail, Slug, ZEB1, ZEB2, and Twist1, as well as its effects on microRNA expression. The review highlights the potential of melatonin as an adjuvant to conventional cancer therapies due to its lack of toxic side effects and its ability to enhance drug efficacy. Additionally, melatonin's role in regulating signaling pathways involved in EMT, such as TGF-β, Wnt/β-catenin, Notch, IL6/STAT3, PI3/AKT, HH-GLI, and receptor tyrosine kinase signaling, is discussed. Overall, melatonin's inhibitory effects on EMT make it a promising candidate for enhancing cancer treatment outcomes.