Tanshinone IIA isolated from Danshen is widely used in Oriental medicine. However, the action of tanshinone IIA in inflammatory bone-resorptive diseases remains unknown. Here we examined the effect of tanshinone IIA in inflammation-mediated osteoclastic bone resorption. Tanshinone IIA inhibited osteoclast differentiation in cocultures of bone marrow cells and calvarial osteoblasts. Tanshinone IIA regulated the expression of receptor activator of NF-κB ligand and osteoprotegerin in osteoblasts treated with lipopolysaccharide (LPS). Also, tanshinone IIA inhibited prostaglandin E2 (PGE2) synthesis by inhibiting Cyclooxygenase-2 (COX-2) expression induced by LPS. Furthermore, tanshinone IIA greatly suppressed bone loss in the mouse models of bone loss. Our findings suggest that tanshinone IIA inhibits osteoclast formation by inhibiting COX-2/PGE2 signaling and by suppressing bone erosion in vivo. These results suggest that tanshinone IIA may be of therapeutic value as an anti-bone-resorptive drug in the treatment of bone-related disease.