Due to the increasing prevalence of bone disorders among people especially in average age, the future of treatments for osseous abnormalities has been illuminated by scaffold-based bone tissue engineering. In this study, in vitro and in vivo properties of 58S bioactive glass-based scaffolds for bone tissue engineering (bare (B.SC), Zein-coated (C.SC), and Zein-coated containing Kaempferol (KC.SC)) were evaluated. This is a follow-up study on our previously published paper, where we synthesized 58S bioactive glass-based scaffolds coated with Kaempferol-loaded Zein biopolymer, and characterized from mostly engineering points of view to find the optimum composition. For this aim, in vitro assessments were done to evaluate the osteogenic capacity and biological features of the scaffolds. In the in vivo section, all types of scaffolds with/without bone marrow-derived stem cells (BMSC) were implanted into rat calvaria bone defects, and potential of bone healing was assessed using imaging, staining, and histomorphometric analyses. It was shown that, Zein-coating covered surface cracks leading to better mechanical properties without negative effect on bioactivity and cell attachment. Also, BMSC differentiation proved that the presence of Kaempferol caused higher calcium deposition, increased alkaline phosphatase activity, bone-specific gene upregulation in vitro. Further, in vivo study confirmed positive effect of BMSC-loaded KC.SC on significant new bone formation resulting in complete bone regeneration. Combining physical properties of coated scaffolds with the osteogenic effect of Kaempferol and BMSCs could represent a new strategy for bone regeneration and provide a more effective approach to repairing critical-sized bone defects.