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• Hinokitiol lowered RANKL-induced osteoclast formation and bone resorption in vitro. • Hinokitiol inhibited early activation of the ERK, p38, and JNK–MAPK pathways. • Hinokitiol also suppressed the activity and expression of c‐Jun, c‐Fos, and NFATC1. • Hinokitiol treatment protected against ovariectomy-induced bone loss in vivo. • Hinokitiol has potential as a novel treatment for osteoclast-induced osteoporosis. Osteoporosis is a metabolic bone-loss disease characterized by abnormally excessive osteoclast formation and bone resorption. Identification of natural medicines that can inhibit osteoclastogenesis, bone resorption, and receptor activator of nuclear factor-κB ligand (RANKL)‐induced signaling is necessary for improved treatment of osteoporosis. In this study, hinokitiol, a tropolone-related compound extracted from the heart wood of several cupressaceous plants, was found to inhibit RANKL-induced osteoclast formation and bone resorption in vitro. Hinokitiol inhibited early activation of the ERK, p38, and JNK–MAPK pathways, thereby suppressing the activity and expression of downstream factors (c‐Jun, c‐Fos, and NFATC1). Consistent with the above in vitro findings, hinokitiol treatment protected against ovariectomy-induced bone loss in vivo. Collectively, our results imply that hinokitiol can potentially serve as an effective agent for treating osteoclast-induced osteoporosis. [ABSTRACT FROM AUTHOR]