Clinical solutions of bone defects caused by periodontitis involve surgical treatment and subsequent anti-infection treatment using antibiotics. Such a strategy faces a key challenge in that the excessive host immune response results in the damage of periodontal tissues. Consequently, it is of great importance to develop novel periodontitis treatment that allows the regulation of the host immune response and promotes the generation of periodontal tissues. Irisin has a good bone regeneration ability and could reduce the inflammatory reaction by regulating the differentiation of macrophages. In this study, we loaded irisin onto bioactive glass nanoparticles (BGNs) to prepare a composite, irisin-BGNs (IR-BGNs) with anti-inflammatory, bacteriostatic, and tissue regeneration functions, providing a novel idea for the design of ideal materials for repairing oral tissue defects caused by periodontitis. We also verified that the IR-BGNs had better anti-inflammatory properties on RAW264.7 cells compared to irisin and BGNs alone. Strikingly, when hPDLCs were stimulated with IR-BGNs, they exhibited increased expression of markers linked to osteogenesis, ALP activity, and mineralization ability in comparison to the negative control. Furthermore, on the basis of RNA sequencing results, we validated that the p38 pathway can contribute to the osteogenic differentiation of the IR-BGNs. This work may offer new thoughts on the design of ideal materials for repairing oral tissue defects.