Balance between bone-resorbing osteoclats and bone-forming osteoblasts is important in bone homeostasis. In particular, increased osteoclast formation and activity are responsible for bone diseases such as osteoporosis, rheumatoid arthritis, periodontal disease. Natural metabolites of plants have recently received much attention as lead compounds for the development of novel therapeutic strategy. The purpose of this study was to search the natural products to inhibition osteoclast differentiation. Water extract of papaya significantly inhibited receptor activator of nuclear factor-KB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages (BMMs) in a dose dependent manner. However, water extract of papaya did not affect cytotoxicity when compared with control. Water extract of papaya inhibited the phosphorylation of p38 and JNK induced by RANKL. The mRNA expression of c-Fos, NFATcl, TRAP and OSCAR induced by RANKL was inhibited by water extract of papaya treatment. Also, water extract of papaya suppressed the protein expression of c-Fos and NFATcl in BMMs treated with RANKL. Taken together, these results suggest that papaya may be a useful drug in the treatment of bone-related disease.