To design and prepare a novel controlled release system for sustained release of two drugs. In this study, a double-layer microsphere was incorporated with strontium-doped calcium polyphosphate (SCPP) scaffold to facilitate bone regeneration and achieve skull repair. The double-layer microsphere combining tetracycline loaded sodium alginate and matrix metalloproteinase-2 (MMP-2) loaded chitosan was manufactured by electrospinning, which were further adhered to SCPP scaffold. The characteristics of microstructure were observed through scanning electron microscope. Loading efficiencies and the optimal ratio of microsphere of the obtained controlled release system were investigated. In addition, the cytotoxicity and the effects on osteoblast proliferation and expressions of osteogenesis-related factors were examined in vitro. Thereafter, the compound material with the controlled release system was implanted in the skull defect of rabbit to evaluate its properties of promoting bone regeneration. The results indicated that this novel controlled release system with SCPP scaffold and the double-layer microspheres loaded with tetracycline and MMP-2 could be a promising material for bones repair.