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Hydrogels are extracellular-matrix-like biomimetic materials that have wide biomedical applications in tissue engineering and drug delivery. However, most hydrogels cannot simultaneously fulfill the mechanical and cell compatibility requirements. In the present study, we prepared a semi-interpenetrating network composite gel (CG) by incorporating short chain chitosan (CS) into a covalent tetra-armed poly(ethylene glycol) network. In addition to satisfying physicochemical, mechanics, biocompatibility, and cell affinity requirements, this CG easily encapsulated acetylsalicylic acid (ASA) via electrostatic interactions and chain entanglement, achieving sustained release for over 14 days and thus promoting periodontal ligament stem cell (PDLSC) proliferation and osteogenic differentiation. In vivo studies corroborated the capacity of PDLSCs and ASA-laden CG to enhance new bone regeneration in situ using a mouse calvarial bone defect model. This might be attributed to PDLSCs and host mesenchymal stem cells expressing monocyte chemoattractant protein-1, which upregulated M2 macrophage recruitment and polarization in situ , indicating its appealing potential in bone tissue engineering., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors.)