Estrogen-related receptor γ(ERRγ), a member of the orphan nuclear receptor family, is a key mediator in cellular metabolic processes and energy homeostasis. Therefore, ERRγ has become an attractive target for treating diverse metabolic disorders. We recently reported that ERRγacts as a negative regulator of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. In the present study, we explored the effects of an ERRγ-specific modulator, GSK5182, on ERRγ-regulated osteoclast differentiation and survival. Interestingly, GSK5182 increased ERRγprotein levels similar to GSK4716, which is known as an ERRγagonist. GSK5182 inhibited osteoclast generation from bone marrow-derived macrophages without affecting cytotoxicity. GSK5182 also attenuated RANKL-mediated expression of c-Fos and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), pivotal transcription factors for osteoclastogenesis. Arrested osteoclast differentiation was associated with reduced RANK expression, but not the M-CSF receptor, c-Fms. GSK5182 strongly blocked the phosphorylation of IκBα, c-Jun N-terminal kinase, and extracellular signal-regulated kinase in response to RANKL. GSK5182 also suppressed NF-κB promoter activity in a dose-dependent manner. In addition to osteoclastogenesis, GSK5182 accelerated osteoclast apoptosis by caspase-3 activation. Together, these results suggest that GSK5182, a synthetic ERRγmodulator, may have potential in treating bone resorption-related disorders.