Rare earth nanomaterials, especially those incorporating neodymium, hold great potential for bone regeneration, but their clinical application is limited by insufficient understanding of immunomodulatory effects and potential toxicity concerns. To address this, we developed neodymium-doped mesoporous silica nanoparticles (NDMSN) to modulate macrophage autophagy and polarization. NDMSN exhibited uniform dispersion with an average size of 103 nm. NDMSN displayed low cytotoxicity in M0 macrophages and effectively suppressed pro-inflammatory responses in M1 macrophages. This was evidenced by the inhibition of pro-inflammatory markers (IL-6, IL-1β, and iNOS) and the promotion of anti-inflammatory markers (IL-4, IL-10, and CD206). Autophagy activation was confirmed by upregulated expression of P62, LC3A, BECLIN1, and ATG7, and the anti-inflammatory effects were attenuated upon autophagy inhibition with 3-methyladenine, highlighting autophagy's essential role. Conditioned medium from NDMSN-treated M1 macrophages exhibited pro-angiogenic activity in human umbilical vein endothelial cells by enhancing tube formation and elevating angiogenic gene expression, while showing pro-osteogenic potential in mouse bone marrow mesenchymal stromal cells. In vivo, NDMSN mitigated LPS-induced bone destruction in a mouse calvarial osteolysis model and suppressed osteoclast differentiation. Its osteogenic capacity was further validated in a zebrafish calvarial defect model. These findings demonstrate that NDMSN is a promising immunomodulatory and osteogenic nanomaterial, offering a novel therapeutic strategy for bone regeneration.