The prevalence and mortality rate of colorectal cancer have been dramatically rising globally. Currently, colorectal cancer is emerging as the fourth leading cause of death and the third most common malignancy worldwide. The major drawback in colorectal cancer treatment is related to severe adverse events of both chemotherapy and radiation therapy that lead to toxicity and inflammation. Recently, melatonin as an antioxidant, immune-stimulant, and antimutagenic agent has been noticed. Different studies worked on the molecular role of melatonin on carcinogenesis progression. Overall, the anticancer activity of melatonin, combined with its actions via multiple signaling pathways, is considered hugely exciting to use this drug as a possible treatment strategy to cure cancer. Apart from its anticancer potential, this drug has shown to induce modulation of chemotherapy toxicity and improving its therapeutic efficacy. The present review aimed to discuss the possible role of melatonin usage in management of colorectal cancer.