Iguratimod is a novel disease-modifying antirheumatic drug which is widely used in China. Recent evidence showed that iguratimod attenuated Walker 256 rat mammary gland carcinoma cells induced bone destruction and osteoclasts formation in vivo. Thus, we presumed that iguratimod may suppress osteoclastogenesis and prevent osteoclast-related diseases including postmenopausal osteoporosis. In this study, ovariectomized (OVX) mice were used to detect the effects of iguratimod in vivo. Bone marrow mononuclear cells (BMMCs) were cultured to detect the effects of iguratimod on receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis in vitro and the molecular mechanisms involved. The results demonstrated that iguratimod prevented ovariectomy-induced bone loss by suppressing osteoclast activity. Consistently, iguratimod suppressed RANKL-induced osteoclastgenesis and bone resorption. Furthermore, iguratimod inhibited RANKL-stimulated tumor necrosis factor receptor-associated factor 6 (TRAF6) - transforming growth factor β-activated kinase-1 (TAK1) complex formation, followed by suppressing the activation of downstream mitogen-activated protein kinase (MAPK), NF-κB and c-fos. Iguratimod subsequently decreased the expression of osteoclast-specific genes via targeting nuclear factor of activated T cells c1 (NFATc1). In conclusion, our results clearly show that iguratimod can inhibit OVX-induced bone loss and osteoclastogenesis through modulating RANKL signaling. Therefore, iguratimod may be used as a novel therapy to mitigate postmenopausal osteoporosis.