Gasdermin D (GSDMD)-mediated pyroptosis induces immunogenic cell death and promotes inflammation. However, the functions of GSDMD in tissue homeostasis remain unclear. Here, we identify a physiological function of GSDMD in osteoclasts via a non-lytic p20-generated protein, which prevents bone loss to maintain bone homeostasis. In the late stage of RANKL-induced osteoclastogenesis, GSDMD underwent cleavage, which is dependent on RIPK1 and caspase-8/-3, to yield this p20 product. Gsdmd -deficient osteoclasts showed normal differentiation but enhanced bone resorption with excessive lysosomal activity. Mice with complete or myeloid-specific Gsdmd deletion exhibited increased trabecular bone loss and more severe aging/ovariectomy-induced osteoporosis. GSDMD p20 was preferentially localized to early endosomes and limited endo-lysosomal trafficking and maturation, relying on its oligomerization and control of phosphoinositide conversion by binding to phosphatidylinositol 3-phosphate (PI(3)P). We have thus identified an anti-osteoclastic function of GSDMD as a checkpoint for lysosomal maturation and secretion and linked this to bone homeostasis and endosome-lysosome biology. [Display omitted] • RANKL induces non-pyroptotic GSDMD p20 cleavage during osteoclastogenesis • GSDMD deficiency boosts osteoclastic lysosome function and aggravates bone loss • GSDMD p20 is localized to early endosomes and limits endo-lysosomal maturation • GSDMD p20 function depends on its oligomerization and restriction of PtdIns conversion Li et al. report a non-pyroptotic GSDMD p20 cleavage in osteoclasts, which is dependent on RIPK1/caspase-8/caspase-3. GSDMD deficiency enhances osteoclastic lysosome function and aggravates trabecular bone loss. GSDMD p20 oligomerizes and restricts PtdIns(3)P-PtdIns(3,5)P2 conversion to limit endo-lysosomal maturation for osteoclastic resorption. [ABSTRACT FROM AUTHOR]