This study aims at preparing electrospun PVA NFs incorporating simvastatin/chitosan nanoparticles (SIM CS NPs) as a controlled drug eluting scaffold for bone regeneration. Optimization was performed by Design Expert® software through establishing two factor, three level factorial design, where the independent variables were the applied voltage, flow rate and PVA solution/SIM CS NPs ratio. Formulation variables values for the optimized formula were 18KV, 0.5 mL/h, and 3:1 respectively. NFs diameter and mesh pore size were chosen as the dependent variables. The optimized NFs were evaluated morphologically, chemically, and physically. Additionally, in-vitro SIM release from the scaffolds was investigated along 24 days. Optimum NFs possessed 136 nm diameter size and 6.5 nm porosity. Also, they showed sustained SIM release for 24 days to achieve the desired goal in bone regeneration. The optimized NFs were implanted within induced bone defects in rabbits. In-vivo assessments were performed through cone beam computed tomography 3D images, bone density measurements, histological analysis and bone morphogenetic protein 2 (BMP 2) level. The obtained results proved the high potential of the optimized NFs in promoting bone regeneration compared to untreated group, non-medicated NFs group, free SIM group and NFs loaded with SIM group after 6 weeks of implantation.