Cardiovascular events among patients with chronic kidney disease (CKD) are associated with vascular calcification (VC). Nevertheless, the process of vascular calcification is complicated. A mechanism of VC is cellular osteogenic transdifferentiation. The mechanism through which bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exo) relieve VC is unknown. For the purpose of this study, we used human aortic vascular smooth muscle cells (HA-VSMCs) stimulated by high phosphate to investigate how BMSC-Exo works. Cell calcification was detected by Alizarin red S staining, AKP activity analysis, and the Ca2+ concentration test. The dual-luciferase reporter gene assays were utilized to confirm the targeting link between miR-15a-5p, miR-15b-5p, and miR-16-5p (miR-15a/15b/16) and nuclear factors of activated T cells 3 (NFATc3). The expression of osteogenic transdifferentiation biomarkers was detected using Western blot and RT-qPCR. Based on our findings, miR-15a/15b/16 plays a crucial role in BMSC-Exo's inhibitory effects on calcification and osteogenic transdifferentiation. We then confirmed that miR-15a/15b/16 specifically target the 3'UTR of NFATc3 mRNA and that three miRNAs are more effective than one miRNA. Moreover, we found that down-regulation of NFATc3 could inhibit osteocalcin (OCN) expression, thereby inhibiting the osteogenic transdifferentiation and calcification of HA-VSMCs. This study found that BMSC-Exo plays a role in calcification inhibition by transferring miR-15a/15b/16 and inhibiting their common target gene NFATc3, which down-regulates OCN expression and thus inhibits HA-VSMC osteogenic transdifferentiation. This study identifies a novel target for therapeutic therapy of CKD-VC.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.