Bone defects are usually treated with bone grafting. Several synthetic biomaterials have emerged to replace autologous and allogeneic bone grafts, but there are still shortcomings in bone regeneration. Melatonin has demonstrated a beneficial effect on bone metabolism with the potential to treat fractures, bone defects and osteoporosis. The hormone has been found to promote osteogenesis, inhibit osteoclastogenesis, stimulate angiogenesis and reduce peri-implantitis around the graft. Recently, a growing number of studies have shown beneficial effects of melatonin to treat bone defects. However, cellular and molecular mechanisms involved in bone healing are still poorly understood. In this review, we recapitulate the potential mechanisms of melatonin, providing a new horizon to the clinical treatment of bone defects.