Background: The overactivation of the osteoclasts is a key pathological factor in osteoporosis. Myeloid zinc finger 1 (MZF1) belongs to the scan-zinc finger family, which is involved in multiple processes of tumor malignant progression and is an important transcription factor regulating the expression of osteoblasts. However, the exact role of MZF1 in osteoclasts has not been determined. In this study, the purpose of our study was to elucidate the role of MZF1 in osteoclastogenesis. Results: First, In vivo studies have shown that MZF1 defciency led to decreased bone mass and exhibited a low bone mass osteoporosis phenotype. Further, RANKL-induced osteoclast differentiation in vitro showed larger TRAP-positive osteoclasts and more complete sealing zone in the MZF1-knockout group. Mechanistically, the results showed that MZF1 deletion group promoted the expression of osteoclast-associated genes. MZF1 knockout can regulate RANKL-induced ferroptosis of osteoclasts by regulating Nrf2/GPX4 signaling pathway in the early stage of cell differentiation. Conclusions: Our research revealed that MZF1 knockout promote osteoclast differentiation by regulating iron metabolism and exhibited osteolysis models. This may be a useful therapeutic target for the prevention and treatment of osteolytic diseases.