Objective To investigate the impact of curculigoside (CUR) on autophagy of osteoblasts in rats with osteoporosis (OP) and its regulatory effect on the lncRNA MEG3/miR-181a-5p signal axis. Methods Bone marrow mesenchymal stem cells (BM-MSCs) were cultured in vitro to induce osteoblast differentiation, and the concentration of CUR was screened by CCK-8 method; the database was applied to predict the binding sites of lncRNA MEG3 to miR-181a-5p; BM-MSCs were grouped into NC group, CUR group, CUR+3-MA group, CUR+pc-NC group, and CUR+pc-LncRNA MEG3 group using transfection technology, the expression levels of lncRNA MEG3 and miR-181a-5p were detected by qRT-PCR, alkaline phosphatase (ALP) staining was applied to detect the ALP activity of the cells, the number of autophages was detected by MDC method, immunofluorescence assay was applied to detect the expression of microtubule associated protein 1-light chain 3 (LC3) and autophagy effector protein (Beclin1) . OP rats were established by intramuscular injection of dexamethasone sodium phosphate, and the rats were grouped into control group (CT group), model group (OP group), and OP+CUR group (15 mg/kg CUR by gavage), CT was applied to detect the morphology of the tibial bone in rats, Western blot and qRT-PCR were applied to detect the expression of LC3 Ⅱ/Ⅰ, Beclin1, and lncRNA MEG3, miR-181a-5, respectively. Results The concentration of CUR above 25 μg/mL obviously increased the proliferation activity of BM-MSCs cells (P＜0.05) ; LncRNA MEG3 and miR-181a-5p had targeted binding sites; compared with NC group, the activity of ALP, the number of autophages, and the expression of LC3 and Beclin1 in CUR group increased (P＜0.05) ; compared with the CUR group, the activity of ALP, the number of autophages, and the expression of LC3 and Beclin1 in the CUR+3-MA group decreased (P＜0.05) ; compared with the CUR+pc-NC group, the activity of ALP, the number of autophages, and the expression of LC3 and Beclin1 in the CUR+pc-LncRNA MEG3 group decreased (P＜0.05) . The bone morphological evaluation and the expression of LC3 II/I, Beclin1, miR-181a-5p in OP group were lower than those in CT group, while the expression of lncRNA MEG3 was increased (P＜0.05) ; the bone morphological evaluation and the expression of LC3 II/I, Beclin1, miR-181a-5p in the OP+CUR group were higher than those in the OP group, while the expression of lncRNA MEG3 was lower (P＜0.05) .Conclusion CUR may promote autophagic activity of osteoblasts in OP rats by regulating the LncRNA MEG3/miR-181a-5p signal axis. [ABSTRACT FROM AUTHOR]