Glucocorticoids (GCs) inhibit the resorptive capacity of the osteoclast by disrupting its cytoskeleton. We find that calpain‐6 (Capn6), a unique, nonproteolytic member of its family, is suppressed 12‐fold by dexamethasone (DEX) in the bone‐degrading cell. While Capn6 abundance parallels commitment of naive bone marrow macrophages (BMMs) to the osteoclast phenotype, its excess or deletion does not affect the cell's differentiation. On the other hand, Capn6 localizes to the sealing zone, and its overexpression promotes osteoclast spreading and large actin ring formation, eventuating in stimulated bone degradation. Conversely, Capn6 knockdown impairs cytoskeletal organization and the cell's resorptive capacity. Capn6 complexes with tubulin, and its absence inhibits microtubule acetylation and stability in the osteoclast. Knockdown of Capn6 also reduces β₃‐integrin subunit protein, another essential regulator of osteoclast cytoskeletal function. Reflecting Capn6 as a target molecule of GCs, microtubule stability and acetylation, as well as the expression of β₃‐integrin protein, are similarly suppressed in DEX‐treated osteoclasts. Moreover, overexpression of Capn6 rescues GC‐mediated disruption of osteoclast cytoskeleton. Thus Capn6 promotes cytoskeletal organization and microtubule stability in osteoclasts, and its inhibition may mediate the resorption‐arresting properties of GCs. © 2011 American Society for Bone and Mineral Research.