Background <p>Postmenopausal osteoporosis (PMO), a metabolic bone disorder from estrogen deficiency, disrupts the balance between bone resorption and formation. Its severe consequence, osteoporotic fractures (OPF), significantly increases disability and mortality, severely impacting patients’ quality of life. Elevated miR-642a-3p has been identified in both PMO and bone loss. This research aims to further explore the role of miR-642a-3p in predicting PMO development and OPF risk, along with its underlying mechanisms.</p> Results <p>The research enrolled 127 PMO patients and 91 healthy volunteers (HV). And further subdivided the PMO group into osteoporotic fractures (<i>n</i> = 62) subgroup and without fractures (OPNF, <i>n</i> = 65) subgroup. The results indicate that miR-642a-3p was significantly upregulated in both the PMO and OPF groups. MiR-642a-3p demonstrated good predictive performance for PMO occurrence and OPF risk. High miR-642a-3p expression was identified as an independent risk factor for progression from PMO to OPF. Downregulation of miR-642a-3p not only stimulated osteoblast proliferation but also mitigated associated inflammation and oxidative stress. Furthermore, INO80 is targeted and regulated by miR-642a-3p.</p> Conclusion <p>MiR-642a-3p may have potential as a biomarker for future clinical prediction of PMO and OPF. Inhibition of miR-642a-3p promotes osteoblast proliferation, associated inflammation, and oxidative stress by upregulation of INO80 expression.</p>