Localization of recombinant human bone morphogenetic protein-2 (rhBMP-2) with continuous and effective osteogenic stimulation is still a great challenge in the field of bone regeneration. To achieve this aim, rhBMP-2 was tethered on chondroitin sulfate (CS)-functionalized calcium phosphate cement (CPC) scaffolds through specific noncovalent interactions. CS, one of the core glycosaminoglycans, was covalently conjugated onto CPC scaffolds with the assistance of polydopamine (PDA) and further immobilized rhBMP-2 in a biomimetic form. The CPC-PDA-CS scaffolds not only controlled the release kinetics and presentation state of rhBMP-2 but also effectively increased the expression levels of bone morphogenetic protein receptors (BMPRs) and enhanced the recognitions of the remaining rhBMP-2 to BMPRs. Strikingly, the rhBMP-2-loaded CPC-PDA-CS significantly promoted the cellular surface translocation of BMPRs (especially BMPR-IA). In vivo studies demonstrated that, compared with the rhBMP-2 upon CPC and CPC-PDA, the rhBMP-2 upon CPC-PDA-CS exhibited sustained release and induced high quality and more ectopic bone formation. Collectively, these results suggest that rhBMP-2 can be localized within CS-functionalized CPC scaffolds and exert continuous, long-term, and effective osteogenic stimulation. Thus, this work could provide new avenues in mimicking bone extracellular matrix microenvironment and localizing growth factor activity for enhanced bone regeneration.