Osteoporosis (OP) is a common and fracture-prone skeletal disease featured by deteriorated trabecular microstructure and pathologically involves various forms of regulated bone cell death. However, the role and regulatory mechanisms of ferroptosis in OP are not fully understood. Our study showed marked iron deposition, ferroptosis, and a core anti-ferroptotic factor GPX4 (glutathione peroxidase 4) suppression in OP femurs of ovariectomized (Ovx) mice, coinciding with Gpx4 promoter hypermethylation and elevated DNMT1/3a/3b levels. In addition, KLF5, along with the transcriptional corepressors NCoR and SnoN, induces binding to the hypermethylated GPX4 promoter in osteoporotic femurs sensitive to DNMT inhibition. Conversely, DNMT inhibition with SGI-1027 reversed hypermethylation and GPX4 suppression, reducing the ferroptotic and osteoporotic damage. In cultured primary bone cells, ferric ammonium citrate (FAC) mimicking iron loading similarly induced GPX4 suppression and ferroptosis in osteoblasts, but not in osteoclasts, which were rescued by siRNA-mediated individual knockdown of DNMT 1/3a/3b respectively. Intriguingly, SGI-1027 relieved the ferroptotic alterations induced by FAC, but not by a GPX4 inactivator RSL3. More importantly, we generated a strain of osteoblast-specific Gpx4 haplo-deficient mice (Gpx4+/-) that developed spontaneous ferroptotic OP alterations and further demonstrated that GPX4 inactivation by RSL3 or osteoblastic GPX4 haplo-deficiency largely abrogated the anti-ferroptotic and osteoprotective effects of SGI-1027. Together, our data suggest that the DNMT aberration-incurred epigenetic GPX4 suppression and the resultant osteoblastic ferroptosis contribute significantly to OP pathogenesis and the strategies preserving GPX4 by DNMT intervention is potentially effective to treat OP and the related bone disorders.