Melatonin (N-acetyl-5-methoxytryptamine, MEL) is a hormone produced by the pineal gland that was discovered many years ago. The physiological roles of this hormone in the body are varied. The beneficial effects of MEL administration may be related to its influence on mitochondrial physiology. Mitochondrial dysfunction is considered an important factor in various physiological and pathological processes, such as the development of neurodegenerative and cardiovascular diseases, diabetes, various forms of liver disease, skeletal muscle disorders, and aging. Mitochondrial dysfunction induces an increase in the permeability of the inner membrane, which leads to the formation of a permeability transition pore (mPTP) in the mitochondria. The long-term administration of MEL has been shown to improve the functional state of mitochondria and inhibit the opening of the mPTP during aging. It is known that MEL is able to suppress the initiation, progression, angiogenesis, and metastasis of cancer as well as the sensitization of malignant cells to conventional chemotherapy and radiation therapy. This review summarizes the studies carried out by our group on the combined effect of MEL with chemotherapeutic agents (retinoic acid, cytarabine, and navitoclax) on the HL-60 cells used as a model of acute promyelocytic leukemia. Data on the effects of MEL on oxidative stress, aging, and heart failure are also reported.