Osteolysis is a serious complication of several chronic inflammatory diseases and is closely associated with a local chronic inflammatory reaction with a variety of causes. However, similarities exist in the mechanisms of their pathological processes. Inflammatory factors and oxidative stress-induced nuclear factor B (NF-B) and mitogen-activated protein kinases (MAPKs) signaling pathways play a center role in bone erosion. Dihydromyricetin (DMY) is a natural compound with anti-inflammatory and antioxidative effect, which are commonly used in chronic pharyngitis and alcohol use disorders. In the current study, we identified that DMY attenuated lipopolysaccharide (LPS)-induced oxidative stress through inhibiting the production of reactive oxygen species (ROS) and nitric oxide (NO), downregulated COX-2 and iNOS, and promoted the activity of the antioxidative system by activating superoxide dismutase (SOD) and Nrf2/HO-1 pathway. To further investigate the underlying mechanism, we found that DMY inhibits osteoclast (OC) differentiation and bone resorption activity through blocking the RANKL-induced activation of the NF-B and MAPKs signaling pathways and then downregulated c-Fos and NFATc1, which is essential for OC differentiation. Furthermore, DMY inhibited LPS-induced osteolysis in vivo. Collectively, these results indicate that DMY might be a promising prophylactic antiosteoclastic/resorptive agent in preventing or treating bone lysis diseases.