Neobavaisoflavone (NBIF) is a flavonoid, which has a variety of pharmacological activities. However, the mechanism of NBIF in the treatment of osteoporosis still needs further exploration. The differentiation of osteoblast MC-3T3-E1 cells after treatment was observed by Alizarin red staining. Cell counting kit-8 and flow cytometry were used to detect viability, apoptosis, and reactive oxygen species (ROS) levels of treated MC-3T3-E1 cells, respectively. Malondialdehyde (MDA), lactate dehydrogenase (LDH), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were tested by ELISA kits. The expressions of lncRNA MALAT1, MEG3, CRNDE, Runx2, osteocalcin (OCN), osteopontin (OPN), collagen I (col-I), nuclear Nrf2, cytoplasm Nrf2, heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO1) in treated MC-3T3-E1 cells were examined by Quantitative real-time PCR or Western blot. Dexamethasone (Dex) inhibited the viability of MC-3T3-E1 cells, while the appropriate amount of NBIF had no significantly effect on cell viability. Dex downregulated CRNDE expression, whereas NBIF upregulated CRNDE. Overexpressed CRNDE and NBIF reversed the inhibitory effects of Dex on cell viability, differentiation and levels of SOD, GSH-Px, Runx2, OCN, OPN, col-I, nuclear Nrf2, HO-1 and NQO1 while reversing the promoting effect of Dex on apoptosis and the levels of ROS, MDA, LDH and cytoplasm Nrf2 in MC-3T3-E1 cells, respectively, but shCRNDE further reversed the effects of NBIF in MC-3T3-E1 cells. NBIF protected osteoblasts from Dex-induced oxidative stress by upregulating the CRNDE-mediated Nrf2/HO-1 signaling pathway.© 2021 Wiley Periodicals, LLC.