Objective: To investigate whether M2-type macrophage-derived exosomes (M2-Exo) affect the osteogenic differentiation of lipopolysaccharide (LPS)-stimulated human periodontal ligament stem cells (hPDLSCs) and to elucidate the underlying mechanism. Methods: RAW264.7 macrophages and human periodontal ligament stem cells (hPDLSCs) were used in this study. RAW264.7 cells were induced to polarize into M2-type macrophages, and M2-Exo were extracted and identified by flow cytometry, Western blot (WB), transmission electron microscopy, and other characterization methods. A periodontitis model was established in hPDLSCs by LPS stimulation. Subsequently, M2-Exo were co-cultured with hPDLSCs in osteogenic induction medium, in which the medium was supplemented with fresh M2-Exo regularly during the co-culture period. The effects of M2-Exo on osteogenic differentiation and pyroptosis were evaluated by alkaline phosphatase (ALP) staining, alizarin red S (ARS) staining, WB, and related assays. Nigericin (an NLRP3 agonist) was used for the rescue experiment. Results: M2-type macrophages and M2-Exo were successfully generated and characterized. M2-Exo significantly attenuated LPS-induced suppression of osteogenic differentiation in hPDLSCs, as evidenced by enhanced ALP activity, increased mineralized nodule formation, and upregulated expression of osteogenic markers (P < 0.001). Moreover, M2-Exo alleviated LPS-induced cytotoxicity, reduced pro-inflammatory cytokine levels, and inhibited NLRP3 inflammasome-mediated pyroptosis (P < 0.001). Nigericin abolished the anti-pyroptotic and osteogenic-promoting effects of M2-Exo (P < 0.05). Conclusion: M2-Exo appear to facilitate osteogenic differentiation in LPS-stimulated hPDLSCs through suppression of NLRP3 inflammasome-mediated pyroptosis. However, the underlying regulatory mechanism warrants further validation beyond the current associative data.