BACKGROUND: Postmenopausal osteoporosis is characterized by osteoclast differentiation and bone loss. Tangeretin (TGN) is a natural product that possesses multiple pharmacological properties. However, its specific function in postmenopausal osteoporosis deserves further exploration. METHODS: The in vitro and in vivo models of postmenopausal osteoporosis were established by using BMMs stimulated with M-CSF and RANKL and mice receiving ovariectomized (OVX) operation. Osteoclast-specific gene expression was determined by RT-qPCR. The protein level was detected by Western blotting. H&E staining was performed to observe the pathological changes in murine distal femurs. RESULTS: For in vitro study, TGN did not affect cell viability but downregulated RANKL-stimulated osteoclast-specific gene expression. For in vivo study, TGN not only alleviated OVX-triggered pathological alterations of femur tissue, but also effectively inhibited proteoglycan loss and cartilage injury induced by OVX in the femurs of mice. Additionally, TGN prevented osteoclastogenesis in OVX mice by downregulating TRAP activity and osteoclast-specific gene expression. Mechanistically, TGN significantly inhibited the activation of Notch signaling via the downregulation of Notch-1, Notch-2, Notch-3, Jagged1, Hes-1, and Hey-1 protein levels in vitro and in vivo. CONCLUSION: TGN represses RANKL-induced osteoclastogenesis and alleviates postmenopausal osteoporosis by inhibiting Notch signaling.