Osteosarcoma is the most common bone tumor, which mainly occurs in children and adolescents. It usually occurs at the metaphysis of long bones with the characteristics of late discovery, rapid progression, early invasion and metastasis, and high mortality. Clinically, the treatment of osteosarcoma is mainly surgery, but the curative effect is unsatisfactory. Thus, it has become an urgent clinical issue to improve the survival rate and quality of life of osteosarcoma patients. Melatonin is an indole hormone, and melatonin levels are related to bone formation; deficiency of melatonin may be directly related to osteosarcoma. This article summarizes the recent research progress of melatonin in osteosarcoma treatment to provide new ideas and future directions for the clinical application of melatonin in osteosarcoma treatment.