Tissue engineered bone substitutes should mimic natural bone characteristics to be highly-suitable for treating bone defects in addition to its biocompatibility and good mechanical stability. In this study, we performed a detailed in vivo bone regeneration evaluation of 80 wt% duck’s feet collagen/poly(lactide-co-glycolide) scaffolds (DC/ PLGA) fabricated by solvent casting/salt leaching strategy in a rat calvarial defect as model. We have already shown a strong influence of DC/ PLGA scaffolds on bone regeneration in terms of biomaterial cohesion, architecture, mechanical features, and in vitro biological properties. The as-fabricated scaffold has shown significant increase in osteogenesis, initial bone formation and differentiation, ascribed to the high percentage of DC in the 80 wt% DC/PLGA scaffold. The in vivo implanted scaffold was found be well-attached to the bone defect region and eventually gets integrated with the surrounding tissues without any pronounced inflammatory reactions. Compared to bare PLGA, an increased recovery in bone volume was observed at 8th week post-surgery. Thus, the 80 wt% DC/PLGA scaffold can be envisioned as a potential alternative bone graft in bone tissue engineering.