Regenerative medicine seeks advanced solutions for bone repair in the form of bioactive synthetic scaffolds by using simple and reproducible processing techniques. In this work, poly-ε-caprolactone (PCL)-based porous scaffolds with improved osteoconductive and osteoinductive properties were processed by supercritical foaming through a careful tuning of components and processing conditions. Composite scaffolds were prepared from various combinations of PCL, silk fibroin and nano-hydroxyapatite (nHA). The green and cost-effective supercritical CO2 foaming method applied rendered solid scaffolds with 67–70% porosity. The incorporation of fibroin and nHA in the scaffolds increased the compressive modulus, cellular adhesion and calcium deposition. The composite scaffolds were tested in vivo in a large-scale calvarial defect model, and bone regeneration was evaluated for up to 14 weeks after implantation. Histomorphometric results showed that all implanted constructs gave rise to the endochondral bone formation and unveiled the synergistic effect of silk fibroin and nHA on the bone repair extent. The information gathered may shed light on the design and processing criteria of bioactive bone scaffolds.