Integrating multiple pro-osteogenic factors into bone graft substitutes is a practical and effective approach to improve bone repair efficacy. Here, Si-Zn dual elements and PLGA microspheres were incorporated into calcium phosphate cement (CPC) scaffolds (PLGA/CPC-Si/Zn) as a novel strategy to synergistically enhance bone regeneration. The incorporation of PLGA microspheres and Si/Zn dual elements within CPC scaffolds improved the setting time, injectability and compressive strength. The PLGA/CPC-Si/Zn scaffolds displayed controlled sequential release of Si and Zn ions. In vitro, RAW 264.7 cells displayed the M2 phenotype with a high level of anti-inflammatory cytokines in response to PLGA/CPC-Si/Zn. The conditioned medium of RAW 264.7 cells cultured on the PLGA/CPC-Si/Zn scaffolds significantly enhanced the osteogenic differentiation of rat BMSCs. In a rat femur defect model, the implanted PLGA/CPC-Si/Zn scaffolds led to obvious new bone formation after 4 weeks, apparent bone ingrowth into the PLGA microspheres after 12 weeks, and was almost completely filled with mature new bone upon degradation of the PLGA microspheres at 24 weeks. These findings demonstrate that the PLGA/CPC-Si/Zn scaffolds promote osteogenesis by synergistically improving the immune microenvironment and biodegradability. Hence, integrating multiple trace elements together with degradable components within bone graft biomaterials can be an effective strategy for promoting bone regeneration.