Chemoinformatic and bioassay-guided fractionation of a gorgonian coral Junceella juncea resulted in the isolation of 45 briarane-type diterpenoids, of which 16 new analogues were characterized. Their structures were identified by extensive analyses of the spectroscopic data. Most isolated briaranes showed significant inhibition against the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in bone marrow-derived macrophages cells (BMMs). Praelolide, one of the active analogs, significantly activates nuclear factor erythroid-2-related factor 2 (Nrf2) nucleus translocation, induces the expression of Nrf2-targeted genes, suppresses reactive oxygen species (ROS) production, abrogates the activation of downstream mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NFκB) signaling, and subsequently attenuates osteoclast differentiation. Mechanically, praelolide interacts with Kelch-like ECH-associated protein 1 (Keap1) protein by non-covalent interaction to interrupt the interaction between Keap1 and Nrf2 and thereby to activate the Nrf2 signaling pathway. In addition, praelolide rescues the bone loss in prednisone-induced zebrafish. The present study provided praelolide as a new natural scaffold to remedy osteoclastogenic bone disease.