© 2019 Elsevier B.V.The aim of this study is to develop a scaffold-based device in which both osteoinductive and anticarcinogenic properties of melatonin can be combined for osteosarcoma therapy. While a high melatonin concentration and fast release are needed to achieve an anticancer effect, a low melatonin concentration and long-term release are necessary for bone regeneration. Long-term controlled release of melatonin was provided by the incorporation of melatonin-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles into the chitosan/hydroxyapatite (chitosan/HAp) scaffolds. This system showed a biphasic melatonin release-pattern with a burst release within 24 h, and then, a sustained release for 40 days that resulted into ∼40–70 μM concentration. Preosteoblastic MC3T3-E1 cells were cultured on this 3D device, and released melatonin caused increase in the expressions of osteogenic differentiation markers. For the inhibition of MG-63 human osteosarcoma cells, a melatonin/2-hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complex was prepared by microwave technology to load a high amount of melatonin and provide fast release. Melatonin/HPβCD inclusion complex was incorporated into the chitosan/HAp scaffolds and loaded melatonin was rapidly released within 5 h and inhibited the proliferation of MG-63 cells in the G0/G1 phase. In conclusion, this melatonin-releasing scaffold-based device including melatonin-loaded PLGA microparticles and melatonin/HPβCD inclusion complex can be considered as a promising system for osteosarcoma therapy.