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Purpose: Advances in the design and manufacturing of novel synthetic bioactive scaffolds as bone substitute in bone reconstruction are at the forefront of orthopedic study due to their excellent biological performances. However, fabricating bioactive scaffolds with similar osteogenic and mechanical properties of a natural bone still remains a challenge. Our aim was to produce functional bioactive scaffolds with biologically interactive ions, microstructure for cell proliferation and a suitable biodegradation rate in critical-size bone defect. Methods: A homogenous strontium-doped calcium silicate (Sr-CaSi) bioactive granule with interconnected porous network was fabricated. Critical-size bone defect (Ø ~6.5 × 8.5 mm) was created at the distal femur of New Zealand rabbit and the animals were divided into two groups (blank group and implanted/Sr-CaSi group). The blank had no granules while the implanted group was grafted with Sr-CaSi granules at the defect. Bone repair was assed using investigations of micro-CT, 3D argumentation and histological evaluations. Results: The Sr-CaSi group had complete bone healing and reconstruction. The granule showed physiochemical tolerance and was able to biodegrade enhancing the formation of new bone matrix and remodeling. However, the blank group had limited proliferation and osteogenic differentiation of new bone tissue, hence there was retarded ingrowth of new bone tissues. Conclusion: The Sr-CaSi group saw excellent bone mineralization due to biostimulation effect of the bioceramic granules. The extensive stimulation and osteogenic factors in bone healing by the novel Sr-CaSi shows it is indispensable in bone tissue engineering and regenerative medicine. [ABSTRACT FROM AUTHOR]