The potential of injectable hydrogels based on natural polysaccharides (NPH) for repairing significant bone defects seems promising. Yet their osteogenic, angiogenic, and mechanical characteristics fall short of expectations. To overcome these disadvantages of chitosan-based hydrogels, silk fibroin-coated magnesium oxide nanoparticles (SF-MgO-NPs) were integrated into fabricated aqueous-soluble phosphocreatine-functionalized chitosan (CMP) solution to create a CMP@SFMgO-NPs injectable hydrogel via supramolecular assembly. This hydrogel's phosphocreatine acts as a reservoir to regulate Mg2+ release and as a location for supramolecular interaction with MgO-NPs. Injectable CMP@SF-MgO hydrogels encouraged in vitro calcium phosphate (CaP) deposition, ALP activity, and proliferation to MC3T3-E1 cells. This hydrogel (CMP@SF-MgO-NPs(5)) was also highly effective in stimulating the growth of new bone in calvarial lesions of critical size in rats. Therefore, the injectable hydrogel made of CMP@S-MgO-NPs shows promising potential for bone regeneration.