Purpose The repair and treatment of infected bone defects (IBD) is a common challenge faced by orthopedic clinics, medical materials science, and tissue engineering. Methods Based on the treatment requirements of IBD, we utilized multidisciplinary knowledge from clinical medicine, medical materials science, and tissue engineering to construct a high-efficiency vancomycin sustained-release system with nanodiamond (ND) and prepare a composite scaffold. Its effect on IBD treatment was assessed from materials, cytology, bacteriology, and zoology perspectives. Results The results demonstrated that the Van-ND-45S5 scaffold exhibited an excellent antibacterial effect, biocompatibility, and osteogenesis in vitro. Moreover, an efficient animal model of IBD was established, and a Van-ND-45S5 scaffold was implanted into the IBD. Radiographic and histological analyses and bone repair-related protein expression, confirmed that the Van-ND-45S5 scaffold had good biocompatibility and osteogenic and anti-infective activities in vivo. Conclusion Collectively, our findings support that the Van-ND-45S5 scaffold is a promising new material and approach for treating IBD with good antibacterial effects, biocompatibility, and osteogenesis.