Polymethoxyflavonoids (PMFs) are found in citrus fruits, and exert various biological activities. We have previously reported that citrus-derived PMFs showed preventive effects in animal models with bone-resorptive diseases. However, the disadvantage of natural citrus-derived PMFs is the cost associated with high purification. In this study, chemically-synthesized 100% pure PMFs, nobiletin and heptamethoxyflavone, were synthesized, and we examined the effects of synthetic nobiletin (sNobi) and heptamethoxyflavone (sHMF) on osteoclastic bone resorption. In mouse calvarial organ cultures, sNobi and sHMF attenuated the osteoclastic bone resorption elicited by IL-1. Both sNobi and sHMF suppressed the osteoclast formation induced by IL-1 in co-cultures of mouse bone marrow cells and osteoblasts. In osteoblasts, sNobi and sHMF suppressed IL-1-dependent PGE₂ production, which is critical for inflammatory bone resorption. These synthetic PMFs also acted on osteoclast precursor cells and suppressed the RANKL-dependent differentiation of macrophages into mature osteoclasts. Synthetic PMFs, sNobi and sHMF, may be useful low-cost compounds that can be used in the prevention and treatment of various bone-related diseases.