Ischemic osteonecrosis (ION) can produce permanent deformity and osteoarthritis in the femoral head and other joints. No biologic treatment has been established, and the molecular mechanisms involved in the pathogenesis of ION have not been elucidated. In this work, we found that treatment with sirtuin6 (Sirt6) suppressed inflammatory cytokines, bone resorption, progression of osteoarthritis, and reduced bone deformity in an ION mouse model. We used a deacetylase mutant adenovirus to confirm that those effects were caused by the deacetylase function of Sirt6. Among the osteoclastogenic factors of osteoblasts, only the receptor activator of NF‐κb ligand (RANKL) level changed in response to Sirt6 knockout in primary osteoblasts. In particular, the vitamin D receptor physically interacted with Sirt6 and induced recruitment of Sirt6 around RANKL promoters. Finally, Tg mice overexpressing Sirt6 resisted osteocyte death, bone resorption, and progression of osteoarthritis after ischemic surgery, whereas osteoblast/osteocyte‐specific Sirt6 knockout mice showed aggravated bone loss and severe deformity. Our findings demonstrate that administration of Sirt6 prevents bone loss and osteoarthritis in ischemic conditions. Activation of Sirt6 in osteoblasts/osteocytes could be a new therapeutic approach to treating ION of the femoral head and other bone regions.