We have previously shown that water extract of deer antler (WEDA) inhibited RANKL-mediated osteoclast differentiation from bone marrow macrophages by suppressing c-Fos and NFATc1 expression. Thus, we examined the effect of WEDA in inflammation-induced bone loss in vivo. Here we found that WEDA inhibited osteoblast-supported osteoclast differentiation induced by lipopolysaccharide (LPS). However, WEDA did not suppress the expression of receptor activator of NF-${kappa}B$ ligand (RANKL) in response to LPS in osteoblasts. WEDA also inhibited the bone resorptive activity of mature osteoclasts. To examine the effect of WEDA on bone loss, when LPS injected subcutaneously in mice, bone loss was greatly increased, but WEDA treatment inhibited LPS-mediated bone loss. Taken together, we conclude that WEDA inhibited osteoclast differentiation and bone resorption in vitro and in vivo. Thus WEDA may be useful in the treatment of bone-related disorders.