Cancer remains the leading cause of death worldwide. The treatment of cancer has become increasing complex. Current treatment options for cancer include surgical resection, chemotherapy, radiotherapy, nanomedicine, and immunotherapy. Recent experimental and clinical studies have provided substantial evidence supporting the potential use of melatonin as a preventive and therapeutic agent in oncology. Melatonin (N-acetyl-5-methoxy-tryptamine), a pleiotropic and multitasking molecule, is secreted from the pineal gland during the night under normal light-dark conditions. Beyond its role in circadian regulation, melatonin exhibits antioxidant, anti-aging, immunomodulatory, and anti-cancer properties. Melatonin exerts significant apoptotic, angiogenic, oncostatic, and anti-proliferative effects on a variety of cancer cells. This review discusses the influence of melatonin on cancer cells through mechanisms involving cell cycle regulation, stimulation of apoptosis, autophagy induction, epigenetic modification, and transcriptional regulation.