A microbially-induced inflammatory periodontal disease is the main initiator to disrupt the periodontium. It is desirable to develop a newly guided bone regeneration (GBR) scaffold to accomplish the periodontal tissue regeneration for the concurrent control of inflammation. A novel therapeutic solution for GBR based on 3D multifunctional scaffolds, which combines the merits of osseous regeneration and local anti-inflammatory drug delivery, has been developed. The 3D dual-drug delivery scaffold (DDDS) loaded with parthenolide and naringin was successfully developed by thermally-induced phase separation techniques. The DDDS was hierarchically interconnected to the porous PLLA scaffold loaded with the hydrophobic parthenolide. In addition, the hydrophilic naringin loaded in chitosan microspheres was embedded in the scaffold. In vitro drug release profile results revealed that the DDDS showed an efficient sequential controlled release pattern with parthenolide delivered rapidly, followed by naringin delivered in a more sustained manner. Cell viability of MC3T3-E1 showed a combined effect of dual-drug delivery. Hemolysis of the DDDS was 1.84 +/- 0.44%, which is less than that of the pure PLLA scaffold. To further evaluate the in vivo guided bone regeneration effect of the DDDS, a rat fenestration defect model was generated. The defects were harvested after 4 and 8 weeks for micro-CT and histological observation. The results suggested that the DDDS group had significantly increased the regenerated bone volume fraction compared to both the control and PLLA groups at 8 weeks, which was in parallel with the reduced expression of IL-6. This DDDS, as a GBR scaffold, might be utilized as a novel adjunctive treatment in periodontitis.