Background: Periodontitis leads to tooth loss, which is associated with bone loss due to osteoclast differentiation. Exosomes play a key role in periodontitis. M2-polarized macrophages exhibit anti-inflammatory activity. This study aimed to explore whether M2 macrophages released exosomes (M2-exos) regulated osteoclastogenesis and the mechanisms. Methods: After isolating M2-exos and identifying them, they were treated with the RANKL-induced raw264.7 cells. Osteoclast differentiation was assessed using tartrate resistant acid phosphatase staining assay and quantitative real-time PCR (qPCR). The underlying mechanisms of M2-exos were evaluated using qPCR and western blotting. Results: The results indicated that M2-exos suppressed osteoclast differentiation induced by RANKL. CSF2 was highly expressed in M2 macrophages, and knockdown of CSF2 further enhanced the inhibitory effects of M2-exos on osteoclast differentiation. CSF2 positively regulated TNF-α signaling, which inhibition also enhanced the role of M2-exos. Conclusion: M2-exos inhibited RANKL-induced osteoclast differentiation by downregulating the CSF2/TNF-α axis. The findings provide theoretical support for the application of macrophage exosomes in the treatment of periodontitis