Cadmium (Cd), is a highly toxic environmental pollutant, which seriously threatens the health of poultry and humans. The occurrence of osteoporosis is the main manifestation of cadmium toxicity. Pyroptosis plays an important role in the development of osteoporosis. Melatonin has been shown to affect preserving bone health. However, the underlying mechanism has not been elucidated. In the present study, these functions of melatonin have been investigated in duck bone tissue and osteoblast during cadmium exposure. In vivo, the studies suggest that melatonin protects against cadmium-induced duck osteoporosis by improving the osteogenesis function, inhibiting bone resorption, and suppressing the occurrence of pyroptosis. In vitro, the findings demonstrated that melatonin alleviated the inhibition effect of cadmium on duck bone marrow-derived mesenchymal stem cells (BMSC) osteogenic differentiation, and suppressed the cadmium-induced osteoclast differentiation. In addition, we also found that melatonin prevents cytokines release of lactate dehydrogenase (LDH), interleukin-18 (IL-18), and interleukin-1β (IL-1β) by cadmium-induced, and reduces the expression of n-terminal Gasdermin D (N-GSDMD), alleviates the osteoblast death rate. In short, melatonin as a potential therapeutic agent has bright prospects in cadmium-induced bone toxicity.